PMCCPMCCPMCC

Search tips
Search criteria 

Advanced

 
Logo of nihpaAbout Author manuscriptsSubmit a manuscriptNIH Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
 
Exp Neurol. Author manuscript; available in PMC Jun 1, 2011.
Published in final edited form as:
PMCID: PMC2864344
NIHMSID: NIHMS140013
Neurogenesis and Alzheimer's disease: At the crossroads
Orly Lazarov1$ and Robert A. Marr2,3
1Department of Anatomy and Cell Biology, College of Medicine, The University of Illinois at Chicago, Chicago, IL 60612
2Department of Neuroscience, Rosalind Franklin University of Medicine and Science, North Chicago, IL 60064
3Center for Stem Cell and Regenerative Medicine, Rosalind Franklin University of Medicine and Science, North Chicago, IL 60064
$ Address Correspondence to: Orly Lazarov, Ph.D., Assistant Professor of Neuroscience, Department of Anatomy and Cell Biology, College of Medicine, 808 S Wood St. M/C 512, University of Illinois at Chicago, Chicago, IL 60612, (Voice) 312-355-0548, olazarov/at/uic.edu
While a massive and progressive neuronal loss in specific areas such as the hippocampus and cortex unequivocally underlies cognitive deterioration and memory loss in Alzheimer's disease, noteworthy alterations take place in the neurogenic microenvironments, namely, the subgranule layer of the dentate gyrus and the subventricular zone. Compromised neurogenesis presumably takes place earlier than onset of hallmark lesions or neuronal loss, and may play a role in the initiation and progression of neuropathology in Alzheimer's disease. Neurogenesis in the adult brain is thought to play a role in numerous forms and aspects of learning and memory and contribute to the plasticity of the hippocampus and olfactory system. Misregulated or impaired neurogenesis on the other hand, may compromise plasticity and neuronal function in these areas and exacerbate neuronal vulnerability. Interestingly, increasing evidence suggests that molecular players in Alzheimer's disease, including PS1, APP and its metabolites, play a role in adult neurogenesis. In addition, recent studies suggest that alterations in tau phosphorylation are pronounced in neurogenic areas, and may interfere with the potential central role of tau proteins in neuronal maturation and differentiation. On the other hand, numerous neurogenic players, such as Notch-1, ErbB4 and L1 are substrates of α- β- and γ- secretase that play a major role in Alzheimer's disease. This review will discuss current knowledge concerning alterations of neurogenesis in Alzheimer's disease with specific emphasis on the cross-talk between signaling molecules involved in both processes, and the ways by which familial Alzheimer's disease-linked dysfunction of these signaling molecules affect neurogenesis in the adult brain.
Keywords: Neurogenesis, Alzheimer's disease, tau, amyloid precursor protein, presenilin, stem cells, brain plasticity, LDL receptors
Alzheimer's disease (AD) is characterized by a progressive memory loss and cognitive decline [For review see (Caselli et al., 2006)]. Hippocampus-dependent memory (Rosen et al., 1984; Haxby et al., 1992; Jacobs et al., 1995) and olfaction-dependent memory (Warner et al., 1986; Albers et al., 2006; Serby, 1987; Kesslak et al., 1988;Bacon et al., 1998) are severely impaired in the disease. The vast majority of AD cases are the late onset sporadic form of the disease. While aging is the greatest environmental risk factor for the sporadic form, apolipoprotein E (apoE) genotype is the greatest known genetic risk factor [For review see (Ashford, 2004; Bu, 2009)]. Rare, familial, early- onset autosomal dominant forms of Alzheimer's disease (FAD) are caused by mutations in genes encoding amyloid precursor protein (APP), presenilin-1 (PS1) and presenilin-2 (PS2). PS play a central role in the function of the aspartyl protease γ-secretase complex that cleaves numerous membrane proteins intramembranously, including APP [(De Strooper, 2003) for review see (Selkoe and Wolfe, 2007)]. APP can undergo regulated intramembrane proteolysis (RIP) in at least two pathways known as the non-amyloidogenic and amyloidogenic pathways. In the former, APP first undergoes ectodomain shedding by an enzymatic activity termed α-secretase. While the identity of α-secretase is not fully known, members of the ADAM family and matrix metalloproteases ADAM10 and ADAM17, as well as the aspartyl protease BACE 2 exhibit α-secretase activity in vivo, cleaving APP in the Aβ region. Hampering Aβ formation, this cleavage results in the release of soluble fragment of APP (sAPPα) and the generation of a membrane-bound carboxyl-terminal fragment (CTF) that undergoes a second cleavage event within its transmembrane domain (via RIP) by γ-secretase (see figure 1). γ-secretase is a unique membrane multicomponent protease complex, in which PS are the catalytic core of the enzyme. In the amyloidogenic pathway, APP ectodomain shedding is carried out by the aspartyl protease β-site APP cleaving enzyme I [(BACE1; also known as memapsin and Asp2) (Hussain et al., 1999; Sinha et al., 1999; Vassar et al., 1999; Lin et al., 2000; Yan et al., 1999; Hong et al., 2000). Followed by γ-secretase cleavage, this RIP pathways yields the production of the beta –amyloid peptide (Aβ) and other APP metabolites involved in the progression of AD.
Figure 1
Figure 1
The cross-talk between Alzheimer's disease-linked signals and neurogenic signals
The hallmarks of AD are neurofibrillary tangles, intraneuronal lesions composed of aggregated hyperphosphorylated tau, and amyloid deposition, composed of aggregated Aβ [For review see (Goedert et al., 1991)]. These lesions are evident in and around vulnerable neurons in specific brain areas. The parahippocampal regions are the earliest to be affected [Braak stages I and II,(Braak and Braak, 1985; Braak and Braak, 1996)]. In particular, the entorhino-hippocampal circuit exhibits an early and significant neuropathology. Progressive neuropathology in this area correlates significantly with Braak stages, hippocampal content of abnormally phosphorylated tau (PHF-τ) and degree of dementia as defined by the clinical dementia rating (CDR) scale (Thal et al., 2000). The first morphological and cytoskeletal lesions are in pre-α cells (layer II) of the transentorhinal and entorhinal region that projects to the outer molecular layer of the dentate gyrus (Braak AD stage I). Abnormally phosphorylated tau protein is found in the neuropil of the CA1-subiculum region, followed by the stratum radiatum and stratum oriens, correlating with Braak stage II. In the Braak stages IV and V, the stratum radiatum is fully affected, and the stratum oriens is increasingly affected. Beginning in Braak stage III, tau pathology is prominent in the perforant pathway target zone of the outer molecular layer of the dentate gyrus. Parahippocampal regions and limbic structures, early involved in the course of the disease, have olfactory connections. The primary olfactory cortical targets of the olfactory bulb, the piriform cortex and lateral entorhinal cortex project to the DG, CA3 and CA1 of the hippocampal formation (Lynch et al., 1991). Tau pathology in the olfactory bulb correlates with stage of disease (Attems and Jellinger, 2006) and volume of olfactory bulb and tract inversely correlates with global cognitive performance as determined by the mini-mental state examination [MMSE, (Thomann et al., 2009a; Thomann et al., 2009b)]. Likewise, impaired odor identification correlates with tangles in the entorhinal cortex and CA1/subiculum area of the hippocampus, but not for tangles in other cortical sites (Wilson et al., 2007).
While most of the self-renewal capacity characterizing its embryonic development ceases, the adult mammalian central nervous system retains at least two sites of continuous production of neurons and glial cells: the subventricular zone (SVZ) underneath the walls of the ventricles and the subgranule layer (SGL) of the dentate gyrus (DG) [For review (Alvarez-Buylla and Lim, 2004; Alvarez-Buylla et al., 2002; Lie et al., 2004)]. The SVZ is currently the most robust of the known neurogenic regions in the adult CNS, producing as many as 30,000 new neuroblasts each day in the young adult rats (Alvarez-Buylla et al., 2000). Neuroblasts migrate from the SVZ through the rostral migratory stream (RMS) and populate the olfactory bulb. Approximately 9000 neural stem cells (NSC) are produced daily (or 250,000 NSC per month) in the SGL of the DG of sexually mature, 9-10 weeks old rats, amounting to 0.1% of the population of the entire DG, with a survival rate of about 50% (Cameron and McKay, 2001). Neuroblasts born in these niches migrate out and are able to populate the olfactory bulb (OB) and the granule layer of the DG, respectively, where they differentiate into glial cells and neurons. Newly formed neurons in the GCL send axonal projections to the CA3 subfield of the hippocampus and dendrites to the molecular layer (Zhao et al., 2006). New neurons in the adult hippocampus receive a variety of inputs from existing mature neurons, and preferentially contact and form synapses with preexisting boutons (Toni et al., 2007). It is thought that during maturation, newly formed granule neurons transiently express the Na+-K+-2Cl- transporter NKCC1 for the enhancement of synaptic integration as they form glutamatergic synapses around 2-3 weeks after birth (Ge et al., 2006). Newly generated dentate granule cells have decreased thresholds for activation, increased resting potentials and they undergo long term potentiation more rapidly (van Praag et al., 2002). While the precise physiological functions of neurogenesis, as well as the full spectrum of functional implications of this extent of plasticity in the adult brain are still under intense investigation, it becomes apparent that new neurons that integrate in the hippocampus and olfactory bulb, play important roles in aspects of learning and memory.
Increasing evidence suggests that new neurons play a role in certain forms of brain function involving olfaction- and hippocampal- dependent learning and memory. Studies in mammals using different strains of mice (Kempermann and Gage, 2002), Environmental Enrichment (Kempermann et al., 1997; van Praag et al., 1999), Genetic manipulations (Shimazu et al., 2006; Zhao et al., 2003; Saxe et al., 2006; Zhang et al., 2008a), aged rats [For review see (Bizon and Gallagher, 2005)], stress paradigms (Lemaire et al., 2000), irradiation (Rola et al., 2004; Madsen et al., 2003; Raber et al., 2004) and the DNA methylating agent methylazoxymethanol acetate (MAM; (Shors et al., 2002)), have each shown direct correlations between neurogenesis and performance in spatial memory tasks. Recently, Trouche and colleagues (2009) show that newly integrated neurons in the granule layer of the DG are recruited in a context- and stimulus-specific manner, and contribute to strengthening of memory circuits related to the stimulus given (Trouche et al., 2009). Computational hypotheses have suggested that the turnover of neurons in the DG associated with neurogenesis may provide protection against memory interference when similar items are presented (Becker, 2005; Wiskott et al., 2006). An alternative theory suggests that due to the tendency of newly formed neurons to be easily excitable and more readily undergo long term potentiation, they may be a means by which memories are temporally organized (Aimone et al., 2006). Impairments in neurogenesis may compromise the extent of plasticity of the hippocampus, olfactory system and their associated neural circuits. This could lead to enhanced neuronal vulnerability in these brain areas and functional impairments, such as a reduced capacity for learning and memory. Recent evidence in support of this hypothesis suggests that neurogenesis is impaired in animal models of AD in both SVZ and SGL (Demars et al., 2009). Neurogenic impairments may underlie, at least in part, the progressive loss of memory and compromised ability to learn and process new information characterizing the disease. Both olfactory and hippocampal dysfunction might be enhanced by compromised neurogenesis in the SVZ and SGL of the dentate gyrus, respectively. Most strikingly, molecules central to the pathology of FAD play a regulatory role in aspects of neurogenesis in the embryonic and adult brain, suggesting that dysfunction of these proteins may compromise neurogenic signaling. Here we summarize the recent knowledge on neurogenic roles of molecules that, in their mutated forms cause FAD, and on the dysfunction of neurogenic signaling pathways in AD with consequential alterations in neurogenesis in this disorder.
The neurogenic niche (key pathways)
The neurogenic niche is thought to be a specialized microenvironment within the adult brain, which has the capacity to sustain self-renewal of multipotent NSC and promote their migration, as well as their differentiation into neurons and glia (Ninkovic and Gotz, 2007). Adult progenitor cells derived from nonneurogenic areas exhibit self renewal and multipotentiality once transplanted in a neurogenic brain area, and can differentiate in a region-specific context, suggesting that the microenvironment has a crucial role in providing and regulating fate-determining cues of in the adult brain (Shihabuddin et al., 2000). What makes the SVZ and SGL special in supporting the proliferation and differentiation of multipotent neural progenitors is an area of intensive investigation. It is postulated that endothelial cells and some special astrocytes provide a unique neurogenic niche and have the capability to promote proliferation and neuronal fate determination (Lie et al., 2004; Doetsch, 2003a; Doetsch, 2003b; Lim and Alvarez-Buylla, 1999; Song et al., 2002a). In contrast, astrocytes from nonneurogenic regions, e.g., the adult spinal cord, do not promote either proliferation or neuronal differentiation (Song et al., 2002a). In vivo hot spots of cell proliferation in the SGL are found to be in close proximity to capillaries and astrocytes (Palmer et al., 2000; Seri et al., 2001). It is thought that astrocytes in the neurogenic niche have a broad diversity of functions; some exhibit stem cell characteristics (Seri et al., 2001; Doetsch et al., 1999), some provide neurogenic signals (Lim and Alvarez-Buylla, 1999; Song et al., 2002a), and some provide synaptogenic factors (Song et al., 2002b). The neurogenic niche is believed to play a regulatory role in all steps of NSC maturation (Seidenfaden et al., 2006).
The neurogenic niche is comprised of soluble, membrane-tethered and extracellular matrix signaling molecules expressed by endothelial cells, astrocytes and progenitor cells, as well as ependymal cells in the SVZ niche (Lim et al., 2007). Progenitor cells actively interact with their microenvironment and have the capability to regulate it (Song et al., 2002a; Wurmser et al., 2004; Shen et al., 2004). Numerous signaling pathways, some of which are developmental signals, are implicated in regulation of adult neurogenesis, such as GABA receptors, E2F, Ephrins and Eph receptors, the sonic hedgehog signaling pathway, WNT signaling pathway, Notch 1, neural cell adhesion molecule (NCAM), bone morphogenetic protein (BMP), neurogenesin1 (NG1), noggin, reelin signaling pathway, and paired box 6 (PAX6) (Yoshikawa, 2000; Cooper-Kuhn et al., 2002; Conover et al., 2000; Machold et al., 2003; Machold et al., 2007; Lai et al., 2003; Lie et al., 2005; Amoureux et al., 2000; Grandbarbe et al., 2003; Kohwi et al., 2005; Heinrich et al., 2006; Won et al., 2006; Zhao et al., 2007).
Of particular interest, the Wnt family (Lie et al., 2005; Sato et al., 2004), β-catenin (Chenn and Walsh, 2003; Shimizu et al., 2008) and notch -1 were identified as critical regulators of neurogenensis in the adult brain [Figure 1, For review see (Shi et al., 2008)]. Wnts are made and secreted by astrocytes in the adult hippocampal niche and specifically increase proliferating neuronally-restricted precursor proliferation and differentiation (Lie et al., 2005). Wnt has also been implicated in neurogenesis originating from the SVZ during stroke repair (Morris et al., 2007; Lei et al., 2008). It was suggested that in the adult brain, notch signaling modulates cell cycle time thus enabling self-renewal of NSC (Alexson et al., 2006). Interestingly, Shimizu and colleagues (2008) provide evidence suggesting that glycogen synthase kinase 3 (GSK3) inactivation and β-catenin stabilization by Wnts are essential for the self-renewal of neural stem cells. Noteworthy are the findings that β-catenin promotes neural precursor cell proliferation through the activation of LEF/TCF transcription factors. Interestingly, nuclear accumulated β-catenin also induces antineurogenic hes1 gene expression through the enhancement of Notch1- and RBP-J –mediated transcription. β-catenin can associate with the Notch1 intracellular domain (NICD), and it is present in a nuclear protein-DNA complex containing the hes1 gene promoter. The β-catenin–NICD complex is efficiently formed when transcriptional coactivators p300 and P/CAF both are present (Shimizu et al., 2008).
EGF is a critical growth factor regulating neural progenitor cell proliferation in the SVZ [Figure 1; (Kuhn et al., 1997)]. The cellular response to EGF is initiated by rapid kinetics of receptor activation, followed by phosphorylation-dependent activation of signaling cascades. This is typically analyzed by observing activation of the ERK MAPKs and subsequent transcriptional activation of immediate-early genes [(IEGs), (Amit et al., 2007)]. EGFR is a receptor tyrosine kinase of the ErbB family, critical signaling molecules of cell proliferation and fate determination (Bublil and Yarden, 2007). The epidermal growth factor (EGF) ErbB system is one of the best studied signaling networks. Among all members of the large family of growth factor receptor tyrosine kinases (RTKs), the ErbB family (also called the type I RTKs) is considered the prototypic founder sub-group of the RTK super-family, which includes 18 other small sub-groups of related receptors. Erbb4 is autonomous; when bound by a ligand growth factor it undergoes dimerization and generates intracellular signals culminating in cell proliferation, migration or differentiation (Bublil and Yarden, 2007).
In the SVZ, the neuregulin receptor, ErbB4, is primarily expressed by immature neuroblasts but is also detected in a subset of astrocytes, ependymal cells, and Dlx2+ precursors. Of the neuregulin ligands, both neuregulin-1 and -2 are expressed by immature neuroblasts. ErbB4 activation is thought to be required for neuregulin-1 and -2-mediated regulation of cell proliferation and neuroblast migration in the SVZ (Ghashghaei et al., 2006). ErbB4 regulates neuroblast migration and organization in the RMS (Anton et al., 2004). In the DG, ErbB4 regulates formation of radial glial cells (Zheng and Feng, 2006). All of the above mentioned critical players in the neurogenic niche interact with known mediators of AD pathology, as described in detail in the following paragraphs, providing an intriguing mechanistic link between AD and neurogenesis (Fig. 1).
Alpha secretases in neurogenesis and AD
Members of the disintegrin-metalloproteinases (ADAMs) family and ADAM10 and ADAM17 (TACE) in particular, are thought to have α-secretase activity in vivo (Buxbaum et al., 1998; Asai et al., 2003). Perhaps α-secretase activity is best known for alpha site proteolysis of APP. This processing of APP prevents the production of Aβ and thus potential amyloid pathology, linking α-secretase activity to AD. Interestingly, ADAM10 KO mice die at E9.5 and exhibit multiple brain defects (Hartmann et al., 2002). These mice have a similar phenotype to EGF receptor (EGFR) KO mice or TGFα KO mice (Tropepe et al., 1997), suggesting an important role for ADAM10 in cleavage-dependent activation of these components of EGF signaling (Hinkle et al., 2004; Lee et al., 2003; Sunnarborg et al., 2002). Notch1 and EGF receptor ligands are substrates of ADAM10 (Hartmann et al., 2002; Cornell and Eisen, 2002). Both ADAM10 and 17 are implicated in development-regulated notch signaling by ectodomain shedding of Notch ligands Delta and Jagged (LaVoie and Selkoe, 2003). While localization and function of TACE and ADAM10 in the SVZ have been described (Katakowski et al., 2007; Yang et al., 2006; Yang et al., 2005) their expression by different cell types residing in this neurogenic area is yet to be determined. In that regard, Katakowski and colleagues report that TACE is expressed in isolated and clustered cells in the SVZ, as well as in ependymal cells and cells in contact with the lateral ventricle. They further report that TACE is expressed by SVZ neuroblasts but not astrocytes (Katakowski et al., 2007). Yang and colleagues suggest that ADAM21 is a dominant ADAM family member expressed in the adult SVZ (Yang et al., 2006; Yang et al., 2005). Therefore, it appears that alterations in α-secretase activity would modulate aspects of both neurogenesis and AD.
Another recently identified enzyme exhibiting α-secretase activity is BACE2, a single transmembrane aspartyl protease of 518 amino acids. The coding sequences of BACE2 and the β-secretase-encoding BACE1 are about ~50% identical. Despite extensive studies about the function of BACE1, the function of BACE2 remains unknown. Studies show that BACE2 cleaves APP at the Phe 19 and Phe 20 sites, which are adjacent to the α-secretase cleavage site, suggesting that BACE2 functions as an alternative α-secretase and as an antagonist of BACE1 (Farzan et al., 2000).
α-secretase-like metalloprotease-dependent ectodomain shedding is an event common to numerous neurogenic signals, including insulin-like growth factor-1 (IGF-1) (McElroy et al., 2007), Notch1 (Brou et al., 2000), E-cadherin (Maretzky et al., 2005a), L1 (Maretzky et al., 2005b), ErbB4 (Rio et al., 2000), and EGFR ligands (Sahin et al., 2004). Both ADAM10 and 17 play major roles in the ectodomain shedding of EGFR ligands (Sahin et al., 2004). Soluble APPα (sAPPα), a cleavage product of α-secretase regulates proliferation of EGF-responsive NSC in the SVZ (Caille et al., 2004). Thus, FAD-linked reduction in sAPP levels may affect extent of neural progenitor cell proliferation and the amount of the NSC pool. Likewise, alterations in α-secretase activity may affect neurogenesis.
PS1 regulates embryonic and adult neurogenesis
PS1, a homologue of the C. elegans sel-12, a protein that plays a major role in cell fate decisions (Levitan and Greenwald, 1995; Hong and Koo, 1997), has increasingly been considered an appealing signal in fundamental neurogenic pathways. PS1, like sel-12 in C. elegans, mediates LIN-12/notch signaling. The lin-12 gene mediates multiple cell– cell interactions during uterine–vulval development. In the vulva, lin-12 is required first in the decision between the 1° and 2° vulval precursor cell fate (Sternberg, 1988; Sternberg and Horvitz, 1989), and then for proper vulval morphogenesis (Sundaram and Greenwald, 1993a; Sundaram and Greenwald, 1993b).
PS are thought to be the catalytic core of the aspartyl protease γ-secretase which is required for Aβ production linked to AD pathology. In mammals, PS1/γ-secretase cleaves notch-1 receptor in response to ligand binding followed by an ectodomain shedding cleavage event (LaVoie and Selkoe, 2003; De Strooper et al., 1999; Wong et al., 1997). Notch intracellular domain (NICD) is then liberated, translocates to the nucleus and regulates gene expression. Interestingly, recent studies suggest that notch-1 functions in embryonic and adult neurogenesis are distinct (Alexson et al., 2006).
The first indication that PS1 may play a role in neurogenesis has been provided by experiments in mice with genomic deletions of PSEN1 exhibiting severely abnormal somitogenic and neurogenic processes in the brain (Wong et al., 1997; Shen et al., 1997). The ventricular zone is substantially thinner in the brain of these mice after embryonic day 14.5, indicating a drastic reduction in the number of neural progenitor cells (Shen et al., 1997). In addition, expression of notch-1 and its ligand is dramatically reduced (Wong et al., 1997). The lethality of this mutation has hampered further studies of the role of PS1 in a natural brain setting in postnatal life. That led to the examination of neurogenesis in FAD-linked PS1 transgenic mice. Nevertheless, given the numerous cellular activities in which PS1 is implicated, most currently available transgenic mice offer little advantage when it comes to processes that take place postnatally in restricted brain areas with a unique population of dividing progenitor cells, as transgenes are expressed in a ubiquitously, nonspecific manner. Lack or dysfunction of PS1 in mature neurons in the brain may induce processes that may alter neurogenesis indirectly (Chen et al., 2008).
In addition to notch-1 and APP, RIP of the membrane-anchored carboxyl terminal fragments of the neurogenic signals receptor tyrosine kinases ErbB4 (Ni et al., 2001; Sardi et al., 2006), IGF-1R (McElroy et al., 2007), insulin receptor (Kasuga et al., 2007), L1 (Maretzky et al., 2005b) and E-cadherin (Marambaud et al., 2002) are catalyzed by PS1/γ-secretase. Neuregulin 1 (NRG1)-induced presenilin-dependent ErbB4 nuclear signaling regulates the timing of astrogenesis in the developing brain (Sardi et al., 2006). Upon activation and presenilin-dependent cleavage of ErbB4 juxtamembrane-a (JMa), its intracellular domain (E4ICD) forms a complex with the signaling protein TAB2 and the corepressor N-CoR. This complex translocates to the nucleus of undifferentiated neural precursors and inhibits their differentiation into astrocytes by repressing the transcription of glial genes (Sardi et al., 2006).
Interesting new information is provided by a recent study suggesting that during embryonic development TAG1 binds APP. As a result, levels of the C-terminal intracellular domain of APP, namely, AICD, are upregulated in a γ-secretase-dependent manner, leading to modulation of neurogenesis (Ma et al., 2008). However, information concerning the role of AICD in regulation of adult neurogenesis is largely unknown. Recent studies also suggest that PS1/γ-secretase processing of APP regulates EGFR (Zhang et al., 2007; Li et al., 2007; Repetto et al., 2007). PS1/γ-secretase cleavage of APP results in the generation of AICD, which directly binds to EGFR promoter and regulates EGFR gene expression (Zhang et al., 2007). Therefore, FAD alterations in APP and PS1 processing and/or function may affect EGFR expression and function. Reduced PS1/γ-secretase activity is inversely correlated with EGFR levels in fibroblasts and induces skin tumors (Li et al., 2007). These studies suggest that PS1/γ-secretase plays a role of tumor suppressor in fibroblasts. In that regard, PS1 is implicated as a negative regulator of the Wnt/β-catenin signaling pathway (Xia et al., 2001). Following its cleavage, PS1CTF/NTF forms a complex with GSK3 and β-catenin (Tesco and Tanzi, 2000). Kang and colleagues suggest that PS1 functions as a scaffold that rapidly couples β-catenin phosphorylation through sequential kinase activities independent of the Wnt-regulated Axin/CK1α complex (Kang et al., 2002).
The role of PS1 in neurogenesis may be γ-secretase-dependent, at least in part. Treatment with γ-secretase inhibitor enhances neuronal differentiation of embryonic stem cells (Ma et al., 2008). In addition, treatment with a γ-secretase inhibitor reduces the extent of proliferation of mesenchymal stem cells and alters their differentiation (Vujovic et al., 2007).
APP metabolites in neurogenesis and AD
APP belongs to a family of evolutionary conserved type I membrane proteins, that includes amyloid precursor-like protein 1 and 2 (APLP1 and APLP2) [For review see (Selkoe, 2001)]. The lethality of APP/APLP2 and of APLP1/APLP2 knockout mice revealed that these proteins have crucial developmental and postnatal functions, and suggested functional redundancy between APP and APLP2 (von Koch et al., 1997; Herms et al., 2004). In the central nervous system, increase in APP expression during development overlaps with neuronal differentiation (Hung et al., 1992). Nevertheless, the physiological role(s) of APP and APP metabolites remains largely unknown. Interestingly, soluble APP (sAPP), a cleavage product released following cleavage of APP by α-secretase, has been implicated in regulation of cell proliferation(Saitoh et al., 1989; Slack et al., 1997; Schmitz et al., 2002; Meng et al., 2001; Pietrzik et al., 1998). Recent intriguing information is provided by studies suggesting that the SVZ is a major sAPP binding site, where sAPP regulates proliferation of transit amplifying (type C cells) EGF-responsive cells (Caille et al., 2004; Ohsawa et al., 1999). These cells self-renew in the presence of EGF, and differentiate into neurons and glia upon EGF removal (Morshead et al., 1994). Caille and colleagues show that EGF-induced proliferation of NSC is partly dependent on the EGF-induced release of sAPP into the medium. However, sAPP is necessary but not sufficient, as it does not induce cell division in EGF-free medium (Caille et al., 2004). Taken together with the resemblance between notch and APP processing, it would be tempting to speculate that other metabolites of APP, such as the carboxyl-terminus of APP (APP-CTFs) may play a regulatory role in different aspects of neurogenesis in the adult brain. AICD production has also been linked to AD through the discovery that this transcription factor binds to the neprilysin promoter and induces expression of this Aβ degrading enzyme (Belyaev et al., 2009; Pardossi-Piquard et al., 2005). Recent studies have revealed that Aβ42 enhances the survival and differentiation of progenitor cells (Lopez-Toledano and Shelanski, 2004) or compromise these processes (Haughey et al., 2002a; Calafiore et al., 2006; Mazur-Kolecka et al., 2006; Millet et al., 2005). This controversy may be the result of the use of variable Aβ preparations in vitro, exhibiting differential conformations.
Wnt, reelin and the low-density lipoprotein receptor family in neurogenesis and AD
Polymorphisms in the apolipoprotein E (apoE) gene show the most significant effects on relative genetic risk of sporadic AD. The ε4 isoform (Cyc112-Arg) of apoE is associated with increased risk of developing AD, while ε2 (Arg158-Cys) is associated with protection from the disease compared to the normal ε3 allele (Bu, 2009). This has been reproduced in gene modified mouse models of AD (Bales et al., 1999; Holtzman et al., 2000; Fagan et al., 2002). Furthermore, intrahippocampal lentiviral gene transfer of ε4 and ε2 can respectively promote and prevent AD-like pathology in APP transgenic mice (Dodart et al., 2005). ApoE binds to every member of a class of receptors known as the low-density lipoprotein receptors (LDLR) [reviewed in (Herz, 2001)]. There are upwards of 10 members to this family of receptors. Classically they have been shown to function in cholesterol and lipid transport. However, this large receptor family has also been shown to function as signal transducers (Hoe et al., 2005a). Blocking the LDLR family results in embryonic lethality as a result of the inability to form mesoderm (Herz and Marschang, 2003; Hsieh et al., 2003).
Numerous studies during the last 10 years established that LDLR linked cellular signaling pathways modulate AD pathology [For review see (Qiu et al., 2006)]. Reelin and its homolog F-spondin are recognized by the very-low density lipoprotein receptor (VLDLR) and apolipoprotein E receptor-2 (apoE-R2), two members of the LDLR family. Mice lacking Reelin, double-knockouts lacking VLDLR and ApoER2, and mice lacking disabled-1 (Dab1) display increased levels of phosphorylated tau. It was suggested that the reelin-ApoE receptor complex initiates a signaling cascade that regulates phosphorylation of tau by GSK3 (Ohkubo et al., 2003). F-spondin and recently reelin have been shown to regulate APP processing through their interaction with APP and ApoER-2 (Hoe and Rebeck, 2008; Hoe et al., 2009; Hoe et al., 2005b). ApoER-2 has also been shown to be neuroprotective during aging (Beffert et al., 2006), and F-spondin was reported to protect against Aβ toxicity (Cheng et al., 2009). Finally, reelin expression has recently been shown to be downregulated in APP transgenic mice and in AD (Chin et al., 2007). Other LDLR family members including LRP1, LRP1B, and LR11/sorLA have also been shown to modulate APP processing [For review see (Marzolo and Bu, 2009)]. LRP5 and LRP6 are LDLR family members that function as co-receptors required for Wnt signaling. As discussed above, wnt functions to inhibit GSK3 and so plays a role in modulation of tau phosphorylation in AD. However the effects of wnt on AD pathology are not limited to potential modulation of tau phosphorylation. Lithium, a potent inhibitor of GSK3 activity, was shown to substantially reduce levels of Aβ, in vitro and in vivo (Phiel et al., 2003). RNA interference experiments showed that the α and β isoforms of GSK3 produced opposite effects on Aβ levels indicating a more complex relationship to APP processing (Phiel et al., 2003). Furthermore, it has also been shown that lithium could ameliorate neurodegeneration induced by Aβ fibrils and improve memory performance in rats (De Ferrari et al., 2003). However, the potential effects of lithium on Aβ pathology remain controversial as a more recent publication has contradicted the effect of lithium on Aβ production and memory but confirmed a role in blocking tau pathology in 3×Tg (APP/PS1/tau transgenic) mice (Caccamo et al., 2007). Aβ has been shown to antagonize wnt signaling through the induction of the Dickkopf-1 (Dkk1) Wnt inhibitor producing a potential negative feedback loop promoting AD (Caricasole et al., 2004). Also, recently Dickkopf-1 down regulation by estrogen was found to reduce tau phosphorylation during cerebral ischemia (Zhang et al., 2008b). Lastly, genetic linkage analysis has found an association between the Wnt co-receptor LRP6 and risk of developing AD (De Ferrari et al., 2007).
A more recent study showed that in transgenic mice carrying human ε4 (apoE4) apoptosis of neural progenitor cells takes place after exposure of these mice to environmental enrichment (Levi and Michaelson, 2007) suggesting that at least part of the mechanism by which apoE4 induces susceptibility to AD is by compromising neurogenesis. In addition to apoE there are a variety of LDLR ligands which have been implicated in neurogenesis. Reelin is perhaps the best characterized of these neurogenic factors. Reelin is highly regulated during embryogenesis and functions to guide neuroblasts towards their destinations during lamination of the cortex [For review see (Herz and Chen, 2006)]. During adulthood reelin continues to be expressed from interneurons of the brain and particularly from pyramidal neurons of the entorhinal cortex, which send major projections to the DG, as well as receive projections from CA1 and CA3 regions of the hippocampus (Pesold et al., 1998; Ramos-Moreno et al., 2006). Reelin expression has been shown to mediate the migration of neuroblasts and direct cell fate determination of adult NSC (Heinrich et al., 2006; Won et al., 2006; Zhao et al., 2007; Gong et al., 2007). F-spondin has also been implicated in neuroblast chain formation in the rostral-migratory-stream (Andrade et al., 2007). In summary, increasing evidence points towards a role for numerous LDL receptor ligands and pathways in neurogenesis, most of which are associated with AD, providing further support for a mechanistic link between these processes.
Tau phosphorylation and Kinase activity in neurogenesis and AD
Hyperphosphorylation of tau is one of the earlier events in the formation of neurofibrillary tangles. Recent studies provide interesting information concerning the course of tau pathology in relation to amyloid pathology in the 3×Tg-AD mice (Oddo et al., 2003) and shed new light on the pathological effects of tau hyperphosphorylation and aggregation (Santacruz et al., 2005; Binder et al., 2005). Functional implications of hyperphosphorylation of tau may be far-reaching when it comes to developing neural progenitor cells, affecting mitosis, axonal transport, process elongation and neuronal maturation [For review see (Johnson and Stoothoff, 2004)].
Recent studies suggest that in young APPswe/PS1ΔE9 mice, neural progenitor cell proliferation and early differentiation is impaired in the SVZ, a neurogenic area exhibiting low steady state levels of Aβ but a dramatic increase in tau phosphorylation. Importantly, increase in PHF-1-immunoreactive phosphorylated tau is detected as early as 2 months of age (Demars et al., 2009). The known function-associated phosphorylation sites of tau are reportedly on serine and threonine, suggesting a role for serine and threonine kinases and phosphatases in AD. There are more than ten serine/threonine protein kinases that have been shown to phosphorylate tau in vitro. According to the motif-specificity, these kinases can be divided into two major groups, i.e., the proline-directed protein kinases (PDPKs) and nonproline- directed protein kinases (NPDPKs). Among these kinases, GSK-3β is among the most implicated in the abnormal hyperphosphorylation of tau in AD brains. As discussed above, glycogen synthase kinase 3 (GSK3) is a component of the Wnt signaling pathway, that plays a major role in adult neurogenesis (Lie et al., 2005), microtubule dynamics and fast axonal transport (Frame et al., 2001; Morfini et al., 2002). GSK3 is inactivated by phosphorylation at serine 9 (Ser9) in its N′-terminus. Among GSK3's numerous substrates are PS1, β-catenin, tau, and kinesin-I light chains (KLC) [(Tesco and Tanzi, 2000; Morfini et al., 2002; Takashima et al., 1998) For review see (Frame and Cohen, 2001)]. Previous studies suggest that FAD-linked PS1 mutations affect GSK3 kinase activity in transfected cell lines (Takashima et al., 1998; Weihl et al., 1999a; Weihl et al., 1999b). Significantly, phosphorylation of KLC by GSK3 promotes the release of kinesin-I from membrane-bound organelles, leading to a reduction in fast anterograde axonal transport (Morfini et al., 2002). GSK3 has been recently suggested to play a role in the induction of mammalian neurogenesis in embryonic stem cells and in regulation of neurogenesis in the adult SVZ (Maurer et al., 2007), raising the possibility that alterations in GSK3 kinase activity in the SVZ and SGL microenvironments underlie alterations in tau phosphorylation in these neurogenic niches of adult mice. Wen and colleagues show an interplay between cyclin-dependent kinase 5 (cdk5), previously shown to be central for tau phosphorylation (Noble et al., 2003) and GSK3β in mice overexpressing p25. While cdk5 activity increases APP processing, GSK3β activity induces tau phosphorylation. Interestingly, inhibition of cdk5 activates GSK3β activity (Wen et al., 2008a). Finally, transcriptional regulation of β-secretase by cdk5 was also shown to lead to enhanced amyloidogenic processing of APP (Wen et al., 2008b). Therefore, these kinases may function as a critical focal point for processes that mediate both neurogenesis and AD.
Numerous studies have suggested that the rate of neurogenesis in both SVZ and DG declines with age, raising the possibility that reduced neurogenesis may account, to some degree, for the impaired learning and memory and cognitive deterioration in the elderly (Tropepe et al., 1997; Seki and Arai, 1995; Kuhn et al., 1996; Kempermann et al., 1998; Kempermann et al., 2002). Examination of neurogenesis in brain tissue of AD patients revealed increased expression of immature neuronal marker proteins (Jin et al., 2004a). However, these observations have been challenged recently (Boekhoorn et al., 2006). Other reports suggest that in the aged and AD brain, there is a significant decline in extent of proliferation of progenitor cells and their numbers [For review see (Brinton and Wang, 2006)]. A recent study suggests that levels of stem cell factor (SCF), a hematopoietic growth factor that supports neurogenesis in the brain, are reduced in the plasma and cerebrospinal fluid of individuals affected with AD (Laske et al., 2008).
Information from studies using FAD transgenic animal models seems to be more complex (Table 1). This complexity may result from the numerous FAD-linked variables that affect neurogenesis, as revealed above. In an attempt to better understand the effect of FAD aspects on neurogenesis as they are reflected in the animal models we categorized studies by type of transgene(s) and number of mutation(s) expressed, and then analyzed the experimental settings used in individual studies (Table 1). Most studies which examined hippocampal or SVZ neurogenesis in transgenic mice expressing one or two APP mutation show impaired proliferation of progenitor cells and/or impaired neuronal differentiation in these mice. Thus, for example, using PDAPP mice expressing human V717F mutant APP under control of the PDGF promoter, Donovan and colleagues report a decrease in number of BrdU+ newly-formed cells and in the number of surviving cells in the SGL of the hippocampus. These impairments were evident at one year of age, post-onset of deposition, but not at 2 months of age. Examination of newly-formed BrdU+DCX+ neuroblasts revealed their decrease in the SGL concomitantly with an increase in their number in the granule layer (Donovan et al., 2006), emphasize the necessity for a subregion-specific analysis for the assessment of the numbers of newly-formed cells in the hippocampal microenvironment, as well as the need for cell-lineage specific markers in addition to BrdU for a thorough analysis of neurogenesis. Similar observations were obtained in mice harboring FAD-linked mutant APPswe (double mutation). These studies revealed reduced extent of proliferation of newly formed cells and neuronal differentiation in the SGL of the dentate gyrus (Haughey et al., 2002a) and in the SVZ (Haughey et al., 2002b) in these mice. The APPswe transgene is ~2.5 fold overexpressed compared to endogenous levels, and mice exhibit increased β-secretase activity, resulting in increased levels of β-CTF, Aβ and sAPPβ, concomitantly with lower levels of sAPPα (Thinakaran et al., 1996; Borchelt et al., 1996). All of these APP metabolites are thought to modulate variable aspects of neurogenesis, and thus the results of these studies suggest that alterations in ratios and amounts of these metabolites caused by the Swedish mutation may not be favorable when it comes to neurogenesis. In addition, infusion of 5μl of 1mM Aβ1-42 or Aβ25-35 into the lateral ventricle decreased cell proliferation in the SVZ over the next five days (Haughey et al., 2002b). While the conformation of the Aβ used in this study was not determined, these results suggest that Aβ levels and/or conformation may affect neurogenesis in vivo. In a different study, oligomeric Aβ42 was shown to enhance neuronal differentiation of embryonic and postnatal NSC in vitro (Lopez-Toledano and Shelanski, 2004). Mirochnic and colleagues examined hippocampal neurogenesis in APP23. They observed an increase in cell proliferation, but ultimately a decrease in the number of newly-differentiated neurons (Mirochnic et al., 2009). Interestingly, examination of neurogenesis in transgenic mice expressing three or more mutations in APP observed enhanced cell proliferation and neuronal differentiation in the hippocampus and/or SVZ. This may suggest that increased fibrillogenic properties or expression level of Aβ to the extent exhibited by triple mutation in APP, and APPswe,Ind in particular, enhances proliferation and neuronal differentiation. Thus, for example, Jin and colleagues (2004) used FAD-linked mutant platelet-derived growth factor- (PDGF)-APPSw,Ind transgenic mice, which express human APP isoforms APP695, APP751, and APP770 with both the Indiana (V717F) and Swedish (K670N M671L) mutations, driven by a PDGF promoter. These mice exhibit increased numbers of newly-proliferating cells in the SGL and SVZ pre- and post-onset of amyloid deposition (Jin et al., 2004b). It should be noted that the APPswe,Ind mice exhibit extracellular amyloid deposits beginning at 6–9 months of age, as well as synaptic loss, astrogliosis and microgliosis, all of which do not occur in the APPswe mice, at least not until very late in life (Borchelt et al., 1996). Caution should be taken as for the interpretation of the observations presented in these studies. Thus for example, some of the studies depend on BrdU alone for the assessment of newly formed cells in the SGL and/or SVZ. Such proliferating cells may include glia and/or peripheral immune cells that do not belong to the neural progenitor cell population. In order to determine the fate of neural progenitor cell proliferation in these mice, further examination of neural progenitor cell marker, such as nestin or cell lineage-specific markers should be used.
Table 1
Table 1
Summary of studies examining alterations in neurogenesis in FAD-linked mouse models
In a different study, Lopez-Toledano and colleagues (2007) used PDGF-APPswe,Ind mice, similar to Jin and colleagues (2004). In support of the latter Lopez-Toledano et al. observed an increase in proliferation of hippocampal cells, as well as an increase in their neuronal differentiation. This increase was attributed to detectable levels of oligomeric Aβ (Lopez-Toledano and Shelanski, 2007). In contrast, increased proliferation at later time points, close to onset of deposition or post deposition could not be observed (Lopez-Toledano and Shelanski, 2007). The different regimen of BrdU injection (single injection in Lopez-Toledano and colleagues and repetitive dose for consecutive days in the Jin and colleagues and Haughey and colleague studies) makes the comparison between the different observations challenging, particularly if a change in cell cycle takes place in one of the animal models. Similar observations to Jin and colleagues and Toledano-Lopez and colleagues were observed in a separate study using pPDGF-APPSw,Ind (Gan et al., 2008), suggesting an increase in proliferation and differentiation of hippocampal progenitors in these mice at 2 months of age. Interestingly, in contrast to Jin et al. (2004) and Lopez-Toledano et al. (2007), Gan and colleagues observed a decrease in cell proliferation concomitantly with an increase in neuronal differentiation in transgenic mice at 12 months of age (Gan et al., 2008). Examination of BrdU+ cells in Tg9291 mice expressing three FAD linked mutations: APP(695)swe,dutch,Lnd and aged-matched controls revealed amyloid deposition-dependent increase in the number of proliferating cells in the hippocampus (Kolecki et al., 2008). However, the nature of these cells and their cellular lineage is not clear. Ermini and colleagues observed an increase in the number of new neurons in aged but not in adult (pre-onset of amyloid deposition) in APP23 mice expressing KM670/671NL mutated human APPswe under a murine Thy-1 promoter element. However, a decrease in proliferation of hippocampal neural progenitor cells was found in APPKM670/671NL/PS1L166P mice post onset of deposition (Ermini et al., 2008). Several additional studies examined hippocampal neurogenesis in transgenic mice coexpressing FAD-linked APP and PS1 mutant variants. Thus, for example, in APPswe/PS1ΔE9 mice, a decrease in long-term survival of hippocampal progenitors was detected post onset of deposition (Verret et al., 2007). Long-lasting impairments in hippocampal neurogenesis were detected in APP/PS1 KI mice post onset of deposition (Zhang et al., 2006). Taniuchi and colleagues report a decrease in the number of proliferating cells and of newly-formed neuronal (DCX+) cells in the hippocampus of APPswe/PS1ΔE9 mice at age of 9 months, post amyloid deposition, but not at onset of deposition (5 months) (Taniuchi et al., 2007). In 3×Tg-AD, an age- and gender-dependent reduction in proliferation of hippocampal progenitor cells correlates with number of hippocampal neurons accumulating intracellular Aβ (Rodriguez et al., 2008).
Observations obtained in several transgenic mice expressing FAD-linked mutant PS1 suggest that alterations in neurogenesis in these mice are apparent only following introduction of an external neurogenic stimulus, such as enriched environment. Thus, Choi and colleagues (2008) as well as Feng and colleagues (2001) report impairments in enriched environment-induced neurogenesis, but no impairment without stimulus (Feng et al., 2001; Choi et al., 2008). While Feng and colleagues used a conditional PS1 KO, Choi and colleagues used transgenic mice harboring mutant PS1. These results may suggest that either PS1 plays a role in regulation of the neurogenic response to enriched environment or that without stimulus, the effect of the mutation on neurogenesis is milder. Transgenic mice expressing FAD-linked PS1 P117L that were maintained in either standard housing or environmentally enriched conditions exhibit compromised survival of new neurons. In PS1 P117L mice maintained in standard housing conditions, survival of new astrocytes is compromised as well (Wen et al., 2004). Using PS1M146V knockin mice Wang and colleagues show that the number of newly formed cells and neurons in the hippocampus of these mice is decreased compared to wild type mice and that impaired neurogenesis correlates with deficient associative learning (Wang et al., 2004). In contrast, PS1KO mice rescued with PS1A246 exhibit increased proliferation of newly born cells in the dentate gyrus compared to mice rescued with PS1HWT, but no difference in extent of differentiation (Chevallier et al., 2005).
As described above, the different roles that APP metabolites, PS1 and other critical molecules play in neurogenesis, may account, as least in part, for some of the observed variations in the fate of neurogenesis in the different animal models used in these studies. Importantly, the high responsiveness and sensitivity of neurogenesis to internal and external stimuli may require a careful examination of the data as a function of age, neurodegeneration, extent and onset of amyloidosis, and, other experimental conditions, such as regimen of BrdU injection. Furthermore, differences in behavioral manipulations (e.g. training, and enriched environment) may also account for the observed heterogeneity in observed effects on neurogenesis. For example, notably, two recent studies suggest that induced reduction of amyloidosis enhances neurogenesis. Becker and colleagues show that anti- EFRH immunotherapy (i.e. antibodies raised against the EFRH sequence, encompassing amino acids 3-6 of the 42 residues of the Aβ) reduces amyloid deposition and enhances neurogenesis in PDAPP mice (Becker et al., 2007). Mirochnic and colleagues shows that experience of APP23 in enriched environment enhances neurogenesis, while reducing the ratio of Aβ42/Aβ40 (Mirochnic et al., 2009). While the majority of studies suggest that expression of FAD linked mutations compromise neurogenesis in the adult brain, the reaction of neurogenesis to alterations in the neuronal environment may induce temporally differential extent of neurogenesis. This is demonstrated well in a study of Chen and colleagues, which showed that conditional ablation of PS1 in the forebrain and knock out of PS2 in adult mice (PS1/PS2 KO mice) induces massive neurodegeneration in the cortex and hippocampus. This neurodegeneration is accompanied by induced cell proliferation in the SGL. However, most of these newly formed cells do not survive. In late stages of neurodegeneration the survival of newly generated neurons was severely impaired so that the enhanced neurogenesis could not be detected any more (Chen et al., 2008). This study shows that alterations in neurogenesis are neurodegenerative stage-dependent.
It appears that in the majority of murine studies (12 of 18) neurogenesis is primarily impaired (excluding the conditional knockout studies which are not directly associated with FAD) (Table I). It is interesting to note that studies in which only one naturally occurring mutation of APP and or PS1 are used, a greater majority found impaired neurogenesis (12 of 14). Also, in both cases where only knockin technology was used, an impairment of neurogenesis was found (Wang et al., 2004; Zhang et al., 2006). Conversely, in all cases where mutations in APP were combined (triple or quadruple mutations) increased neurogenesis was found.
Based on the evidence presented above demonstrating that molecular players of FAD, i.e. APP and metabolites, PS1, γ-, α- and potentially β-secretase play a role in neurogenesis, it is reasonable to assume that mutations in these players and/or their dysfunction would compromise neurogenesis in both cell-autonomous and non-cell-autonomous manner. Indeed, recent studies demonstrate that microglia-secreted soluble factors may play a role in regulation of hippocampal neurogenesis, and that microglia derived from the brains of FAD-linked mutant PS1 variants secret altered levels of soluble signaling factors, suggesting a non-cell-autonomous effect of FAD on hippocampal neurogenesis (Choi et al., 2008). This discussion underscores the need to perform studies in which select metabolites are exclusively expressed within, or exclusively secreted from specific cell populations.
In summary, often, seemingly contradicting results were observed in apparently similar animal models. However, as this review reveals, there are numerous players in FAD that may modulate neurogenesis. Neurogenic roles have been attributed to both PS1 and APP. Each APP metabolite alone (e.g., sAPPα, APP-CTFs, p3, Aβ), as well as different conformation and aggregation levels of a given metabolite, such as Aβ, may have unique or specialized role and effect on aspects of neurogenesis. As a consequence, whether a mutation affects β- or γ-secretase activity may modulate neurogenesis differently. In addition, both α- and γ- and possibly β-secretase have numerous neurogenic substrates. Fibrillogenic Aβ levels and concentrations have been shown to have variable effects on neurogenesis. Extent of amyloid deposition and specific pattern of accumulation in the hippocampus may affect neurogenesis differently, as well as astrogliosis, microgliosis, synaptic degeneration and neuronal cell death. Furthermore, the method of neurogenic analysis must be comprehensive and consistent (e.g. BrdU regimen, cell markers, age, etc.) Thus, a thorough understanding of the molecular mechanism underlying AD is required for the analysis of neurogenesis in FAD mouse models. This must be done first before a definite conclusion can be made regarding what is implied for the human disease. Interestingly, it becomes increasingly evident that alterations in neurogenesis take place early in life and may be a contributing factor rather than a result of neural dysfunction. A recent study suggests that in APPswe/PS1ΔE9 transgenic mice, impairments in neurogenesis take place long before amyloid deposition (Demars et al., 2009). Impairments in neurogenesis early in life, prior to processes that secondarily affect neurogenesis, such as neuronal loss, Aβ accumulation, and inflammation, may suggest that expression of FAD-linked proteins directly compromises neurogenesis in the adult brain and contribute to the disease. As AD pathology is progressive, it remains to be determined under what conditions impairment in neurogenesis is causative, at least in part, and under what conditions alterations are a downstream effect of AD pathology. Our summary of the molecular links between neurogenic and AD pathways suggest that neurogenesis is an integral part of AD pathology.
Summary
We have presented evidence that multiple factors known to be intimately involved in AD pathogenesis are now being shown to modulate adult neurogenesis. Most notably PS1 and APP are emerging as a critical player in these processes. Conversely, multiple factors known to be involved in neurogenesis are emerging as critical players in AD pathogenesis. These include Wnt/Notch and reelin signaling. This convergence of signaling should be taken into account in the development of potential therapies.
Figure 2
Figure 2
Adult neural progenitor cells in culture
Acknowledgments
Supported by the Alzheimer's Association Young Investigator Award (OL, RAM), the Illinois Department of Public Health ADRF award (OL), NIA R01AG033570 (OL), and the Alzheimer's disease Drug Discovery Foundation (RAM).
Footnotes
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
  • Caselli RJ, Beach TG, Yaari R, Reiman EM. Alzheimer's disease a century later. The Journal of clinical psychiatry. 2006;67:1784–1800. [PubMed]
  • Rosen WG, Mohs RC, Davis KL. A new rating scale for Alzheimer's disease. The American journal of psychiatry. 1984;141:1356–1364. [PubMed]
  • Haxby JV, Raffaele K, Gillette J, Schapiro MB, Rapoport SI. Individual trajectories of cognitive decline in patients with dementia of the Alzheimer type. Journal of clinical and experimental neuropsychology. 1992;14:575–592. [PubMed]
  • Jacobs DM, Sano M, Dooneief G, Marder K, Bell KL, Stern Y. Neuropsychological detection and characterization of preclinical Alzheimer's disease. Neurology. 1995;45:957–962. [PubMed]
  • Warner MD, Peabody CA, Flattery JJ, Tinklenberg JR. Olfactory deficits and Alzheimer's disease. Biol Psychiatry. 1986;21:116–118. [PubMed]
  • Albers MW, Tabert MH, Devanand DP. Olfactory dysfunction as a predictor of neurodegenerative disease. Curr Neurol Neurosci Rep. 2006;6:379–386. [PubMed]
  • Serby M. Olfactory deficits in Alzheimer's disease. J Neural Transm Suppl. 1987;24:69–77. [PubMed]
  • Kesslak JP, Cotman CW, Chui HC, Van den Noort S, Fang H, Pfeffer R, Lynch G. Olfactory tests as possible probes for detecting and monitoring Alzheimer's disease. Neurobiol Aging. 1988;9:399–403. [PubMed]
  • Bacon AW, Bondi MW, Salmon DP, Murphy C. Very early changes in olfactory functioning due to Alzheimer's disease and the role of apolipoprotein E in olfaction. Ann N Y Acad Sci. 1998;855:723–731. [PubMed]
  • Ashford JW. APOE genotype effects on Alzheimer's disease onset and epidemiology. J Mol Neurosci. 2004;23:157–165. [PubMed]
  • Bu G. Apolipoprotein E and its receptors in Alzheimer's disease: pathways, pathogenesis and therapy. Nature reviews. 2009;10:333–344. [PMC free article] [PubMed]
  • De Strooper B. Aph-1, Pen-2, and Nicastrin with Presenilin Generate an Active gamma-Secretase Complex. Neuron. 2003;38:9–12. [PubMed]
  • Selkoe DJ, Wolfe MS. Presenilin: running with scissors in the membrane. Cell. 2007;131:215–221. [PubMed]
  • Hussain I, Powell D, Howlett DR, Tew DG, Meek TD, Chapman C, Gloger IS, Murphy KE, Southan CD, Ryan DM, Smith TS, Simmons DL, Walsh FS, Dingwall C, Christie G. Identification of a novel aspartic protease (Asp 2) as beta-secretase. Mol Cell Neurosci. 1999;14:419–427. [PubMed]
  • Sinha S, Anderson JP, Barbour R, Basi GS, Caccavello R, Davis D, Doan M, Dovey HF, Frigon N, Hong J, Jacobson-Croak K, Jewett N, Keim P, Knops J, Lieberburg I, Power M, Tan H, Tatsuno G, Tung J, Schenk D, Seubert P, Suomensaari SM, Wang S, Walker D, John V, et al. Purification and cloning of amyloid precursor protein beta-secretase from human brain [see comments] Nature. 1999;402:537–540. [PubMed]
  • Vassar R, Bennett BD, Babu-Khan S, Kahn S, Mendiaz EA, Denis P, Teplow DB, Ross S, Amarante P, Loeloff R, Luo Y, Fisher S, Fuller J, Edenson S, Lile J, Jarosinski MA, Biere AL, Curran E, Burgess T, Louis JC, Collins F, Treanor J, Rogers G, Citron M. Beta-secretase cleavage of Alzheimer's amyloid precursor protein by the transmembrane aspartic protease BACE. Science. 1999;286:735–741. [PubMed]
  • Lin X, Koelsch G, Wu S, Downs D, Dashti A, Tang J. Human aspartic protease memapsin 2 cleaves the beta-secretase site of beta-amyloid precursor protein. Proc Natl Acad Sci U S A. 2000;97:1456–1460. [PubMed]
  • Yan R, Bienkowski MJ, Shuck ME, Miao H, Tory MC, Pauley AM, Brashier JR, Stratman NC, Mathews WR, Buhl AE, Carter DB, Tomasselli AG, Parodi LA, Heinrikson RL, Gurney ME. Membrane-anchored aspartyl protease with Alzheimer's disease beta-secretase activity. Nature. 1999;402:533–537. [PubMed]
  • Hong L, Koelsch G, Lin X, Wu S, Terzyan S, Ghosh AK, Zhang XC, Tang J. Structure of the protease domain of memapsin 2 (beta-secretase) complexed with inhibitor. Science. 2000;290:150–153. [PubMed]
  • Goedert M, Sisodia SS, Price DL. Neurofibrillary tangles and beta-amyloid deposits in Alzheimer's disease. Current opinion in neurobiology. 1991;1:441–447. [PubMed]
  • Braak H, Braak E. On areas of transition between entorhinal allocortex and temporal isocortex in the human brain. Normal morphology and lamina-specific pathology in Alzheimer's disease. Acta Neuropathol (Berl) 1985;68:325–332. [PubMed]
  • Braak H, Braak E. Evolution of the neuropathology of Alzheimer's disease. Acta Neurol Scand Suppl. 1996;165:3–12. [PubMed]
  • Thal DR, Holzer M, Rub U, Waldmann G, Gunzel S, Zedlick D, Schober R. Alzheimer-related tau-pathology in the perforant path target zone and in the hippocampal stratum oriens and radiatum correlates with onset and degree of dementia. Experimental neurology. 2000;163:98–110. [PubMed]
  • Lynch G, Larson J, Staubli U, Granger R. Variants of synaptic potentiation and different types of memory operations in hippocampus and related structures. In: Squire LR, Weinberger NM, Lynch G, McGaugh JL, editors. Memory: Organization and Locus of Change. Oxford University Press; New York: 1991. pp. 330–363.
  • Attems J, Jellinger KA. Olfactory tau pathology in Alzheimer disease and mild cognitive impairment. Clinical neuropathology. 2006;25:265–271. [PubMed]
  • Thomann PA, Dos Santos V, Seidl U, Toro P, Essig M, Schroder J. MRI-derived atrophy of the olfactory bulb and tract in mild cognitive impairment and Alzheimer's disease. Journal of Alzheimer's disease. 2009a;17:213–221. [PubMed]
  • Thomann PA, Kaiser E, Schonknecht P, Pantel J, Essig M, Schroder J. Association of total tau and phosphorylated tau 181 protein levels in cerebrospinal fluid with cerebral atrophy in mild cognitive impairment and Alzheimer disease. Journal of psychiatry & neuroscience. 2009b;34:136–142. [PMC free article] [PubMed]
  • Wilson RS, Arnold SE, Schneider JA, Tang Y, Bennett DA. The relationship between cerebral Alzheimer's disease pathology and odour identification in old age. J Neurol Neurosurg Psychiatry. 2007;78:30–35. [PMC free article] [PubMed]
  • Alvarez-Buylla A, Lim DA. For the long run: maintaining germinal niches in the adult brain. Neuron. 2004;41:683–686. [PubMed]
  • Alvarez-Buylla A, Seri B, Doetsch F. Identification of neural stem cells in the adult vertebrate brain. Brain research bulletin. 2002;57:751–758. [PubMed]
  • Lie DC, Song H, Colamarino SA, Ming GL, Gage FH. Neurogenesis in the adult brain: new strategies for central nervous system diseases. Annual review of pharmacology and toxicology. 2004;44:399–421. [PubMed]
  • Alvarez-Buylla A, Herrera DG, Wichterle H. The subventricular zone: source of neuronal precursors for brain repair. Prog Brain Res. 2000;127:1–11. [PubMed]
  • Cameron HA, McKay RD. Adult neurogenesis produces a large pool of new granule cells in the dentate gyrus. J Comp Neurol. 2001;435:406–417. [PubMed]
  • Zhao C, Teng EM, Summers RG, Jr, Ming GL, Gage FH. Distinct morphological stages of dentate granule neuron maturation in the adult mouse hippocampus. J Neurosci. 2006;26:3–11. [PubMed]
  • Toni N, Teng EM, Bushong EA, Aimone JB, Zhao C, Consiglio A, van Praag H, Martone ME, Ellisman MH, Gage FH. Synapse formation on neurons born in the adult hippocampus. Nat Neurosci. 2007;10:727–734. [PubMed]
  • Ge S, Goh EL, Sailor KA, Kitabatake Y, Ming GL, Song H. GABA regulates synaptic integration of newly generated neurons in the adult brain. Nature. 2006;439:589–593. [PMC free article] [PubMed]
  • van Praag H, Schinder AF, Christie BR, Toni N, Palmer TD, Gage FH. Functional neurogenesis in the adult hippocampus. Nature. 2002;415:1030–1034. [PubMed]
  • Kempermann G, Gage FH. Genetic determinants of adult hippocampal neurogenesis correlate with acquisition, but not probe trial performance, in the water maze task. Eur J Neurosci. 2002;16:129–136. [PubMed]
  • Kempermann G, Kuhn HG, Gage FH. More hippocampal neurons in adult mice living in an enriched environment. Nature. 1997;386:493–495. [PubMed]
  • van Praag H, Christie BR, Sejnowski TJ, Gage FH. Running enhances neurogenesis, learning, and long-term potentiation in mice. Proceedings of the National Academy of Sciences of the United States of America. 1999;96:13427–13431. [PubMed]
  • Shimazu K, Zhao M, Sakata K, Akbarian S, Bates B, Jaenisch R, Lu B. NT-3 facilitates hippocampal plasticity and learning and memory by regulating neurogenesis. Learn Mem. 2006;13:307–315. [PubMed]
  • Zhao X, Ueba T, Christie BR, Barkho B, McConnell MJ, Nakashima K, Lein ES, Eadie BD, Willhoite AR, Muotri AR, Summers RG, Chun J, Lee KF, Gage FH. Mice lacking methyl-CpG binding protein 1 have deficits in adult neurogenesis and hippocampal function. Proc Natl Acad Sci U S A. 2003;100:6777–6782. [PubMed]
  • Saxe MD, Battaglia F, Wang JW, Malleret G, David DJ, Monckton JE, Garcia AD, Sofroniew MV, Kandel ER, Santarelli L, Hen R, Drew MR. Ablation of hippocampal neurogenesis impairs contextual fear conditioning and synaptic plasticity in the dentate gyrus. Proc Natl Acad Sci U S A. 2006;103:17501–17506. [PubMed]
  • Zhang CL, Zou Y, He W, Gage FH, Evans RM. A role for adult TLX-positive neural stem cells in learning and behaviour. Nature. 2008a;451:1004–1007. [PubMed]
  • Bizon JL, Gallagher M. More is less: neurogenesis and age-related cognitive decline in Long-Evans rats. Sci Aging Knowledge Environ. 2005;2005:re2. [PubMed]
  • Lemaire V, Koehl M, Le Moal M, Abrous DN. Prenatal stress produces learning deficits associated with an inhibition of neurogenesis in the hippocampus. Proc Natl Acad Sci U S A. 2000;97:11032–11037. [PubMed]
  • Rola R, Raber J, Rizk A, Otsuka S, VandenBerg SR, Morhardt DR, Fike JR. Radiation-induced impairment of hippocampal neurogenesis is associated with cognitive deficits in young mice. Exp Neurol. 2004;188:316–330. [PubMed]
  • Madsen TM, Kristjansen PE, Bolwig TG, Wortwein G. Arrested neuronal proliferation and impaired hippocampal function following fractionated brain irradiation in the adult rat. Neuroscience. 2003;119:635–642. [PubMed]
  • Raber J, Rola R, LeFevour A, Morhardt D, Curley J, Mizumatsu S, VandenBerg SR, Fike JR. Radiation-induced cognitive impairments are associated with changes in indicators of hippocampal neurogenesis. Radiat Res. 2004;162:39–47. [PubMed]
  • Shors TJ, Townsend DA, Zhao M, Kozorovitskiy Y, Gould E. Neurogenesis may relate to some but not all types of hippocampal-dependent learning. Hippocampus. 2002;12:578–584. [PMC free article] [PubMed]
  • Trouche S, Bontempi B, Roullet P, Rampon C. Recruitment of adult-generated neurons into functional hippocampal networks contributes to updating and strengthening of spatial memory. Proceedings of the National Academy of Sciences of the United States of America 2009 [PubMed]
  • Becker S. A computational principle for hippocampal learning and neurogenesis. Hippocampus. 2005;15:722–738. [PubMed]
  • Wiskott L, Rasch MJ, Kempermann G. A functional hypothesis for adult hippocampal neurogenesis: avoidance of catastrophic interference in the dentate gyrus. Hippocampus. 2006;16:329–343. [PubMed]
  • Aimone JB, Wiles J, Gage FH. Potential role for adult neurogenesis in the encoding of time in new memories. Nat Neurosci. 2006;9:723–727. [PubMed]
  • Demars M, Hu YS, Gadadhar A, Lazarov O. Neurogenesis is impaired early in life in an Alzheimer's disease animal model. 2009 submitted.
  • Ninkovic J, Gotz M. Signaling in adult neurogenesis: from stem cell niche to neuronal networks. Curr Opin Neurobiol. 2007;17:338–344. [PubMed]
  • Shihabuddin LS, Horner PJ, Ray J, Gage FH. Adult spinal cord stem cells generate neurons after transplantation in the adult dentate gyrus. The Journal of neuroscience. 2000;20:8727–8735. [PubMed]
  • Doetsch F. The glial identity of neural stem cells. Nat Neurosci. 2003a;6:1127–1134. [PubMed]
  • Doetsch F. A niche for adult neural stem cells. Curr Opin Genet Dev. 2003b;13:543–550. [PubMed]
  • Lim DA, Alvarez-Buylla A. Interaction between astrocytes and adult subventricular zone precursors stimulates neurogenesis. Proc Natl Acad Sci U S A. 1999;96:7526–7531. [PubMed]
  • Song H, Stevens CF, Gage FH. Astroglia induce neurogenesis from adult neural stem cells. Nature. 2002a;417:39–44. [PubMed]
  • Palmer TD, Willhoite AR, Gage FH. Vascular niche for adult hippocampal neurogenesis. J Comp Neurol. 2000;425:479–494. [PubMed]
  • Seri B, Garcia-Verdugo JM, McEwen BS, Alvarez-Buylla A. Astrocytes give rise to new neurons in the adult mammalian hippocampus. J Neurosci. 2001;21:7153–7160. [PubMed]
  • Doetsch F, Caille I, Lim DA, Garcia-Verdugo JM, Alvarez-Buylla A. Subventricular zone astrocytes are neural stem cells in the adult mammalian brain. Cell. 1999;97:703–716. [PubMed]
  • Song HJ, Stevens CF, Gage FH. Neural stem cells from adult hippocampus develop essential properties of functional CNS neurons. Nat Neurosci. 2002b;5:438–445. [PubMed]
  • Seidenfaden R, Desoeuvre A, Bosio A, Virard I, Cremer H. Glial conversion of SVZ-derived committed neuronal precursors after ectopic grafting into the adult brain. Molecular and cellular neurosciences. 2006;32:187–198. [PubMed]
  • Lim DA, Huang YC, Alvarez-Buylla A. The adult neural stem cell niche: lessons for future neural cell replacement strategies. Neurosurg Clin N Am. 2007;18:81–92. ix. [PubMed]
  • Wurmser AE, Nakashima K, Summers RG, Toni N, D'Amour KA, Lie DC, Gage FH. Cell fusion-independent differentiation of neural stem cells to the endothelial lineage. Nature. 2004;430:350–356. [PubMed]
  • Shen Q, Goderie SK, Jin L, Karanth N, Sun Y, Abramova N, Vincent P, Pumiglia K, Temple S. Endothelial cells stimulate self-renewal and expand neurogenesis of neural stem cells. Science. 2004;304:1338–1340. [PubMed]
  • Yoshikawa K. Cell cycle regulators in neural stem cells and postmitotic neurons. Neurosci Res. 2000;37:1–14. [PubMed]
  • Cooper-Kuhn CM, Vroemen M, Brown J, Ye H, Thompson MA, Winkler J, Kuhn HG. Impaired adult neurogenesis in mice lacking the transcription factor E2F1. Mol Cell Neurosci. 2002;21:312–323. [PubMed]
  • Conover JC, Doetsch F, Garcia-Verdugo JM, Gale NW, Yancopoulos GD, Alvarez-Buylla A. Disruption of Eph/ephrin signaling affects migration and proliferation in the adult subventricular zone. Nat Neurosci. 2000;3:1091–1097. [PubMed]
  • Machold R, Hayashi S, Rutlin M, Muzumdar MD, Nery S, Corbin JG, Gritli-Linde A, Dellovade T, Porter JA, Rubin LL, Dudek H, McMahon AP, Fishell G. Sonic hedgehog is required for progenitor cell maintenance in telencephalic stem cell niches. Neuron. 2003;39:937–950. [PubMed]
  • Machold RP, Kittell DJ, Fishell GJ. Antagonism between Notch and bone morphogenetic protein receptor signaling regulates neurogenesis in the cerebellar rhombic lip. Neural Develop. 2007;2:5. [PMC free article] [PubMed]
  • Lai K, Kaspar BK, Gage FH, Schaffer DV. Sonic hedgehog regulates adult neural progenitor proliferation in vitro and in vivo. Nat Neurosci. 2003;6:21–27. [PubMed]
  • Lie DC, Colamarino SA, Song HJ, Desire L, Mira H, Consiglio A, Lein ES, Jessberger S, Lansford H, Dearie AR, Gage FH. Wnt signalling regulates adult hippocampal neurogenesis. Nature. 2005;437:1370–1375. [PubMed]
  • Amoureux MC, Cunningham BA, Edelman GM, Crossin KL. N-CAM binding inhibits the proliferation of hippocampal progenitor cells and promotes their differentiation to a neuronal phenotype. J Neurosci. 2000;20:3631–3640. [PubMed]
  • Grandbarbe L, Bouissac J, Rand M, Hrabe de Angelis M, Artavanis-Tsakonas S, Mohier E. Delta-Notch signaling controls the generation of neurons/glia from neural stem cells in a stepwise process. Development. 2003;130:1391–1402. [PubMed]
  • Kohwi M, Osumi N, Rubenstein JL, Alvarez-Buylla A. Pax6 is required for making specific subpopulations of granule and periglomerular neurons in the olfactory bulb. J Neurosci. 2005;25:6997–7003. [PubMed]
  • Heinrich C, Nitta N, Flubacher A, Muller M, Fahrner A, Kirsch M, Freiman T, Suzuki F, Depaulis A, Frotscher M, Haas CA. Reelin deficiency and displacement of mature neurons, but not neurogenesis, underlie the formation of granule cell dispersion in the epileptic hippocampus. J Neurosci. 2006;26:4701–4713. [PubMed]
  • Won SJ, Kim SH, Xie L, Wang Y, Mao XO, Jin K, Greenberg DA. Reelin-deficient mice show impaired neurogenesis and increased stroke size. Exp Neurol. 2006;198:250–259. [PubMed]
  • Zhao S, Chai X, Frotscher M. Balance between neurogenesis and gliogenesis in the adult hippocampus: role for reelin. Dev Neurosci. 2007;29:84–90. [PubMed]
  • Sato N, Meijer L, Skaltsounis L, Greengard P, Brivanlou AH. Maintenance of pluripotency in human and mouse embryonic stem cells through activation of Wnt signaling by a pharmacological GSK-3-specific inhibitor. Nature medicine. 2004;10:55–63. [PubMed]
  • Chenn A, Walsh CA. Increased neuronal production, enlarged forebrains and cytoarchitectural distortions in beta-catenin overexpressing transgenic mice. Cerebral cortex (New York, N Y. 2003;13:599–606. [PubMed]
  • Shimizu T, Kagawa T, Inoue T, Nonaka A, Takada S, Aburatani H, Taga T. Stabilized beta-catenin functions through TCF/LEF proteins and the Notch/RBP-Jkappa complex to promote proliferation and suppress differentiation of neural precursor cells. Molecular and cellular biology. 2008;28:7427–7441. [PMC free article] [PubMed]
  • Shi Y, Sun G, Zhao C, Stewart R. Neural stem cell self-renewal. Critical reviews in oncology/hematology. 2008;65:43–53. [PMC free article] [PubMed]
  • Alexson TO, Hitoshi S, Coles BL, Bernstein A, van der Kooy D. Notch signaling is required to maintain all neural stem cell populations—irrespective of spatial or temporal niche. Developmental neuroscience. 2006;28:34–48. [PubMed]
  • Kuhn HG, Winkler J, Kempermann G, Thal LJ, Gage FH. Epidermal growth factor and fibroblast growth factor-2 have different effects on neural progenitors in the adult rat brain. J Neurosci. 1997;17:5820–5829. [PubMed]
  • Amit I, Citri A, Shay T, Lu Y, Katz M, Zhang F, Tarcic G, Siwak D, Lahad J, Jacob-Hirsch J, Amariglio N, Vaisman N, Segal E, Rechavi G, Alon U, Mills GB, Domany E, Yarden Y. A module of negative feedback regulators defines growth factor signaling. Nat Genet. 2007;39:503–512. [PubMed]
  • Bublil EM, Yarden Y. The EGF receptor family: spearheading a merger of signaling and therapeutics. Curr Opin Cell Biol. 2007;19:124–134. [PubMed]
  • Ghashghaei HT, Weber J, Pevny L, Schmid R, Schwab MH, Lloyd KC, Eisenstat DD, Lai C, Anton ES. The role of neuregulin-ErbB4 interactions on the proliferation and organization of cells in the subventricular zone. Proc Natl Acad Sci U S A. 2006;103:1930–1935. [PubMed]
  • Anton ES, Ghashghaei HT, Weber JL, McCann C, Fischer TM, Cheung ID, Gassmann M, Messing A, Klein R, Schwab MH, Lloyd KC, Lai C. Receptor tyrosine kinase ErbB4 modulates neuroblast migration and placement in the adult forebrain. Nat Neurosci. 2004;7:1319–1328. [PubMed]
  • Zheng CH, Feng L. Neuregulin regulates the formation of radial glial scaffold in hippocampal dentate gyrus of postnatal rats. J Cell Physiol. 2006;207:530–539. [PubMed]
  • Buxbaum JD, Liu KN, Luo Y, Slack JL, Stocking KL, Peschon JJ, Johnson RS, Castner BJ, Cerretti DP, Black RA. Evidence that tumor necrosis factor alpha converting enzyme is involved in regulated alpha-secretase cleavage of the Alzheimer amyloid protein precursor. J Biol Chem. 1998;273:27765–27767. [PubMed]
  • Asai M, Hattori C, Szabo B, Sasagawa N, Maruyama K, Tanuma S, Ishiura S. Putative function of ADAM9, ADAM10, and ADAM17 as APP alpha-secretase. Biochem Biophys Res Commun. 2003;301:231–235. [PubMed]
  • Hartmann D, de Strooper B, Serneels L, Craessaerts K, Herreman A, Annaert W, Umans L, Lubke T, Lena Illert A, von Figura K, Saftig P. The disintegrin/metalloprotease ADAM 10 is essential for Notch signalling but not for alpha-secretase activity in fibroblasts. Hum Mol Genet. 2002;11:2615–2624. [PubMed]
  • Tropepe V, Craig CG, Morshead CM, van der Kooy D. Transforming growth factor-alpha null and senescent mice show decreased neural progenitor cell proliferation in the forebrain subependyma. J Neurosci. 1997;17:7850–7859. [PubMed]
  • Hinkle CL, Sunnarborg SW, Loiselle D, Parker CE, Stevenson M, Russell WE, Lee DC. Selective roles for tumor necrosis factor alpha-converting enzyme/ADAM17 in the shedding of the epidermal growth factor receptor ligand family: the juxtamembrane stalk determines cleavage efficiency. J Biol Chem. 2004;279:24179–24188. [PubMed]
  • Lee DC, Sunnarborg SW, Hinkle CL, Myers TJ, Stevenson MY, Russell WE, Castner BJ, Gerhart MJ, Paxton RJ, Black RA, Chang A, Jackson LF. TACE/ADAM17 processing of EGFR ligands indicates a role as a physiological convertase. Ann N Y Acad Sci. 2003;995:22–38. [PubMed]
  • Sunnarborg SW, Hinkle CL, Stevenson M, Russell WE, Raska CS, Peschon JJ, Castner BJ, Gerhart MJ, Paxton RJ, Black RA, Lee DC. Tumor necrosis factor-alpha converting enzyme (TACE) regulates epidermal growth factor receptor ligand availability. J Biol Chem. 2002;277:12838–12845. [PubMed]
  • Cornell RA, Eisen JS. Delta/Notch signaling promotes formation of zebrafish neural crest by repressing Neurogenin 1 function. Development. 2002;129:2639–2648. [PubMed]
  • LaVoie MJ, Selkoe DJ. The Notch ligands, Jagged and Delta, are sequentially processed by alpha-secretase and presenilin/gamma-secretase and release signaling fragments. J Biol Chem. 2003;278:34427–34437. [PubMed]
  • Katakowski M, Chen J, Zhang ZG, Santra M, Wang Y, Chopp M. Stroke-induced subventricular zone proliferation is promoted by tumor necrosis factor-alpha-converting enzyme protease activity. J Cereb Blood Flow Metab. 2007;27:669–678. [PubMed]
  • Yang P, Baker KA, Hagg T. The ADAMs family: coordinators of nervous system development, plasticity and repair. Prog Neurobiol. 2006;79:73–94. [PubMed]
  • Yang P, Baker KA, Hagg T. A disintegrin and metalloprotease 21 (ADAM21) is associated with neurogenesis and axonal growth in developing and adult rodent CNS. J Comp Neurol. 2005;490:163–179. [PubMed]
  • Farzan M, Schnitzler CE, Vasilieva N, Leung D, Choe H. BACE2, a beta -secretase homolog, cleaves at the beta site and within the amyloid-beta region of the amyloid-beta precursor protein. Proc Natl Acad Sci U S A. 2000;97:9712–9717. [PubMed]
  • McElroy B, Powell JC, McCarthy JV. The insulin-like growth factor 1 (IGF-1) receptor is a substrate for gamma-secretase-mediated intramembrane proteolysis. Biochem Biophys Res Commun. 2007;358:1136–1141. [PubMed]
  • Brou C, Logeat F, Gupta N, Bessia C, LeBail O, Doedens JR, Cumano A, Roux P, Black RA, Israel A. A novel proteolytic cleavage involved in Notch signaling: the role of the disintegrin-metalloprotease TACE. Mol Cell. 2000;5:207–216. [PubMed]
  • Maretzky T, Reiss K, Ludwig A, Buchholz J, Scholz F, Proksch E, de Strooper B, Hartmann D, Saftig P. ADAM10 mediates E-cadherin shedding and regulates epithelial cell-cell adhesion, migration, and beta-catenin translocation. Proc Natl Acad Sci U S A. 2005a;102:9182–9187. [PubMed]
  • Maretzky T, Schulte M, Ludwig A, Rose-John S, Blobel C, Hartmann D, Altevogt P, Saftig P, Reiss K. L1 is sequentially processed by two differently activated metalloproteases and presenilin/gamma-secretase and regulates neural cell adhesion, cell migration, and neurite outgrowth. Mol Cell Biol. 2005b;25:9040–9053. [PMC free article] [PubMed]
  • Rio C, Buxbaum JD, Peschon JJ, Corfas G. Tumor necrosis factor-alpha-converting enzyme is required for cleavage of erbB4/HER4. J Biol Chem. 2000;275:10379–10387. [PubMed]
  • Sahin U, Weskamp G, Kelly K, Zhou HM, Higashiyama S, Peschon J, Hartmann D, Saftig P, Blobel CP. Distinct roles for ADAM10 and ADAM17 in ectodomain shedding of six EGFR ligands. J Cell Biol. 2004;164:769–779. [PMC free article] [PubMed]
  • Caille I, Allinquant B, Dupont E, Bouillot C, Langer A, Muller U, Prochiantz A. Soluble form of amyloid precursor protein regulates proliferation of progenitors in the adult subventricular zone. Development. 2004;131:2173–2181. [PubMed]
  • Levitan D, Greenwald I. Facilitation of lin-12-mediated signalling by sel-12, a Caenorhabditis elegans S182 Alzheimer's disease gene. Nature. 1995;377:351–354. [PubMed]
  • Hong CS, Koo EH. Isolation and characterization of Drosophila presenilin homolog. Neuroreport. 1997;8:665–668. [PubMed]
  • Sternberg PW. Lateral inhibition during vulval induction in Caenorhabditis elegans. Nature. 1988;335:551–554. [PubMed]
  • Sternberg PW, Horvitz HR. The combined action of two intercellular signaling pathways specifies three cell fates during vulval induction in C. elegans. Cell. 1989;58:679–693. [PubMed]
  • Sundaram M, Greenwald I. Suppressors of a lin-12 hypomorph define genes that interact with both lin-12 and glp-1 in Caenorhabditis elegans. Genetics. 1993a;135:765–783. [PubMed]
  • Sundaram M, Greenwald I. Genetic and phenotypic studies of hypomorphic lin-12 mutants in Caenorhabditis elegans. Genetics. 1993b;135:755–763. [PubMed]
  • De Strooper B, Annaert W, Cupers P, Saftig P, Craessaerts K, Mumm JS, Schroeter EH, Schrijvers V, Wolfe MS, Ray WJ, Goate A, Kopan R. A presenilin-1-dependent gamma-secretase-like protease mediates release of Notch intracellular domain [see comments] Nature. 1999;398:518–522. [PubMed]
  • Wong PC, Zheng H, Chen H, Becher MW, Sirinathsinghji DJ, Trumbauer ME, Chen HY, Price DL, Van der Ploeg LH, Sisodia SS. Presenilin 1 is required for Notch1 and DII1 expression in the paraxial mesoderm. Nature. 1997;387:288–292. [PubMed]
  • Shen J, Bronson RT, Chen DF, Xia W, Selkoe DJ, Tonegawa S. Skeletal and CNS defects in Presenilin-1-deficient mice. Cell. 1997;89:629–639. [PubMed]
  • Chen Q, Nakajima A, Choi SH, Xiong X, Sisodia SS, Tang YP. Adult neurogenesis is functionally associated with AD-like neurodegeneration. Neurobiol Dis. 2008;29:316–326. [PMC free article] [PubMed]
  • Ni CY, Murphy MP, Golde TE, Carpenter G. gamma -Secretase cleavage and nuclear localization of ErbB-4 receptor tyrosine kinase. Science. 2001;294:2179–2181. [PubMed]
  • Sardi SP, Murtie J, Koirala S, Patten BA, Corfas G. Presenilin-dependent ErbB4 nuclear signaling regulates the timing of astrogenesis in the developing brain. Cell. 2006;127:185–197. [PubMed]
  • Kasuga K, Kaneko H, Nishizawa M, Onodera O, Ikeuchi T. Generation of intracellular domain of insulin receptor tyrosine kinase by gamma-secretase. Biochem Biophys Res Commun. 2007;360:90–96. [PubMed]
  • Marambaud P, Shioi J, Serban G, Georgakopoulos A, Sarner S, Nagy V, Baki L, Wen P, Efthimiopoulos S, Shao Z, Wisniewski T, Robakis NK. A presenilin-1/gamma-secretase cleavage releases the E-cadherin intracellular domain and regulates disassembly of adherens junctions. Embo J. 2002;21:1948–1956. [PubMed]
  • Ma QH, Futagawa T, Yang WL, Jiang XD, Zeng L, Takeda Y, Xu RX, Bagnard D, Schachner M, Furley AJ, Karagogeos D, Watanabe K, Dawe GS, Xiao ZC. A TAG1-APP signalling pathway through Fe65 negatively modulates neurogenesis. Nat Cell Biol. 2008;10:283–294. [PubMed]
  • Zhang YW, Wang R, Liu Q, Zhang H, Liao FF, Xu H. Presenilin/gamma-secretase-dependent processing of beta-amyloid precursor protein regulates EGF receptor expression. Proc Natl Acad Sci U S A. 2007;104:10613–10618. [PubMed]
  • Li T, Wen H, Brayton C, Das P, Smithson LA, Fauq A, Fan X, Crain BJ, Price DL, Golde TE, Eberhart CG, Wong PC. EGFR and notch pathways participate in the tumor suppressor function of gamma -secretase. J Biol Chem. 2007;282:32264–32273. [PubMed]
  • Repetto E, Yoon IS, Zheng H, Kang DE. Presenilin 1 regulates epidermal growth factor receptor turnover and signaling in the endosomal-lysosomal pathway. J Biol Chem. 2007;282:31504–31516. [PubMed]
  • Xia X, Qian S, Soriano S, Wu Y, Fletcher AM, Wang XJ, Koo EH, Wu X, Zheng H. Loss of presenilin 1 is associated with enhanced beta-catenin signaling and skin tumorigenesis. Proc Natl Acad Sci U S A. 2001;98:10863–10868. [PubMed]
  • Tesco G, Tanzi RE. GSK3 beta forms a tetrameric complex with endogenous PS1-CTF/NTF and beta-catenin. Effects of the D257/D385A and FAD-linked mutations. Ann N Y Acad Sci. 2000;920:227–232. [PubMed]
  • Kang DE, Soriano S, Xia X, Eberhart CG, De Strooper B, Zheng H, Koo EH. Presenilin couples the paired phosphorylation of beta-catenin independent of axin: implications for beta-catenin activation in tumorigenesis. Cell. 2002;110:751–762. [PubMed]
  • Vujovic S, Henderson SR, Flanagan AM, Clements MO. Inhibition of gamma-secretases alters both proliferation and differentiation of mesenchymal stem cells. Cell Prolif. 2007;40:185–195. [PubMed]
  • Selkoe DJ. Alzheimer's disease: genes, proteins, and therapy. Physiol Rev. 2001;81:741–766. [PubMed]
  • von Koch CS, Zheng H, Chen H, Trumbauer M, Thinakaran G, van der Ploeg LH, Price DL, Sisodia SS. Generation of APLP2 KO mice and early postnatal lethality in APLP2/APP double KO mice. Neurobiol Aging. 1997;18:661–669. [PubMed]
  • Herms J, Anliker B, Heber S, Ring S, Fuhrmann M, Kretzschmar H, Sisodia S, Muller U. Cortical dysplasia resembling human type 2 lissencephaly in mice lacking all three APP family members. Embo J. 2004;23:4106–4115. [PubMed]
  • Hung AY, Koo EH, Haass C, Selkoe DJ. Increased expression of beta-amyloid precursor protein during neuronal differentiation is not accompanied by secretory cleavage. Proc Natl Acad Sci U S A. 1992;89:9439–9443. [PubMed]
  • Saitoh T, Sundsmo M, Roch JM, Kimura N, Cole G, Schubert D, Oltersdorf T, Schenk DB. Secreted form of amyloid beta protein precursor is involved in the growth regulation of fibroblasts. Cell. 1989;58:615–622. [PubMed]
  • Slack BE, Breu J, Muchnicki L, Wurtman RJ. Rapid stimulation of amyloid precursor protein release by epidermal growth factor: role of protein kinase C. Biochem J. 1997;327(Pt 1):245–249. [PubMed]
  • Schmitz A, Tikkanen R, Kirfel G, Herzog V. The biological role of the Alzheimer amyloid precursor protein in epithelial cells. Histochem Cell Biol. 2002;117:171–180. [PubMed]
  • Meng JY, Kataoka H, Itoh H, Koono M. Amyloid beta protein precursor is involved in the growth of human colon carcinoma cell in vitro and in vivo. Int J Cancer. 2001;92:31–39. [PubMed]
  • Pietrzik CU, Hoffmann J, Stober K, Chen CY, Bauer C, Otero DA, Roch JM, Herzog V. From differentiation to proliferation: the secretory amyloid precursor protein as a local mediator of growth in thyroid epithelial cells. Proc Natl Acad Sci U S A. 1998;95:1770–1775. [PubMed]
  • Ohsawa I, Takamura C, Morimoto T, Ishiguro M, Kohsaka S. Amino-terminal region of secreted form of amyloid precursor protein stimulates proliferation of neural stem cells. Eur J Neurosci. 1999;11:1907–1913. [PubMed]
  • Morshead CM, Reynolds BA, Craig CG, McBurney MW, Staines WA, Morassutti D, Weiss S, van der Kooy D. Neural stem cells in the adult mammalian forebrain: a relatively quiescent subpopulation of subependymal cells. Neuron. 1994;13:1071–1082. [PubMed]
  • Belyaev ND, Nalivaeva NN, Makova NZ, Turner AJ. Neprilysin gene expression requires binding of the amyloid precursor protein intracellular domain to its promoter: implications for Alzheimer disease. EMBO reports. 2009;10:94–100. [PubMed]
  • Pardossi-Piquard R, Petit A, Kawarai T, Sunyach C, Alves da Costa C, Vincent B, Ring S, D'Adamio L, Shen J, Muller U, St George Hyslop P, Checler F. Presenilin-dependent transcriptional control of the Abeta-degrading enzyme neprilysin by intracellular domains of betaAPP and APLP. Neuron. 2005;46:541–554. [PubMed]
  • Lopez-Toledano MA, Shelanski ML. Neurogenic effect of beta-amyloid peptide in the development of neural stem cells. J Neurosci. 2004;24:5439–5444. [PubMed]
  • Haughey NJ, Nath A, Chan SL, Borchard AC, Rao MS, Mattson MP. Disruption of neurogenesis by amyloid beta-peptide, and perturbed neural progenitor cell homeostasis, in models of Alzheimer's disease. J Neurochem. 2002a;83:1509–1524. [PubMed]
  • Calafiore M, Battaglia G, Zappala A, Trovato-Salinaro E, Caraci F, Caruso M, Vancheri C, Sortino MA, Nicoletti F, Copani A. Progenitor cells from the adult mouse brain acquire a neuronal phenotype in response to beta-amyloid. Neurobiol Aging. 2006;27:606–613. [PubMed]
  • Mazur-Kolecka B, Golabek A, Nowicki K, Flory M, Frackowiak J. Amyloid-beta impairs development of neuronal progenitor cells by oxidative mechanisms. Neurobiol Aging. 2006;27:1181–1192. [PubMed]
  • Millet P, Lages CS, Haik S, Nowak E, Allemand I, Granotier C, Boussin FD. Amyloid-beta peptide triggers Fas-independent apoptosis and differentiation of neural progenitor cells. Neurobiol Dis. 2005;19:57–65. [PubMed]
  • Bales KR, Verina T, Cummins DJ, Du Y, Dodel RC, Saura J, Fishman CE, DeLong CA, Piccardo P, Petegnief V, Ghetti B, Paul SM. Apolipoprotein E is essential for amyloid deposition in the APP(V717F) transgenic mouse model of Alzheimer's disease. Proc Natl Acad Sci U S A. 1999;96:15233–15238. [PubMed]
  • Holtzman DM, Bales KR, Tenkova T, Fagan AM, Parsadanian M, Sartorius LJ, Mackey B, Olney J, McKeel D, Wozniak D, Paul SM. Apolipoprotein E isoform-dependent amyloid deposition and neuritic degeneration in a mouse model of Alzheimer's disease. Proc Natl Acad Sci U S A. 2000;97:2892–2897. [PubMed]
  • Fagan AM, Watson M, Parsadanian M, Bales KR, Paul SM, Holtzman DM. Human and murine ApoE markedly alters A beta metabolism before and after plaque formation in a mouse model of Alzheimer's disease. Neurobiol Dis. 2002;9:305–318. [PubMed]
  • Dodart JC, Marr RA, Koistinaho M, Gregersen BM, Malkani S, Verma IM, Paul SM. Gene delivery of human apolipoprotein E alters brain Abeta burden in a mouse model of Alzheimer's disease. Proc Natl Acad Sci U S A. 2005;102:1211–1216. [PubMed]
  • Herz J. The LDL receptor gene family: (un)expected signal transducers in the brain. Neuron. 2001;29:571–581. [PubMed]
  • Hoe HS, Harris DC, Rebeck GW. Multiple pathways of apolipoprotein E signaling in primary neurons. J Neurochem. 2005a;93:145–155. [PubMed]
  • Herz J, Marschang P. Coaxing the LDL receptor family into the fold. Cell. 2003;112:289–292. [PubMed]
  • Hsieh JC, Lee L, Zhang L, Wefer S, Brown K, DeRossi C, Wines ME, Rosenquist T, Holdener BC. Mesd encodes an LRP5/6 chaperone essential for specification of mouse embryonic polarity. Cell. 2003;112:355–367. [PubMed]
  • Qiu S, Korwek KM, Weeber EJ. A fresh look at an ancient receptor family: emerging roles for low density lipoprotein receptors in synaptic plasticity and memory formation. Neurobiol Learn Mem. 2006;85:16–29. [PubMed]
  • Ohkubo N, Lee YD, Morishima A, Terashima T, Kikkawa S, Tohyama M, Sakanaka M, Tanaka J, Maeda N, Vitek MP, Mitsuda N. Apolipoprotein E and Reelin ligands modulate tau phosphorylation through an apolipoprotein E receptor/disabled-1/glycogen synthase kinase-3beta cascade. Faseb J. 2003;17:295–297. [PubMed]
  • Hoe HS, Rebeck GW. Functional interactions of APP with the apoE receptor family. J Neurochem. 2008;106:2263–2271. [PubMed]
  • Hoe HS, Lee KJ, Carney RS, Lee J, Markova A, Lee JY, Howell BW, Hyman BT, Pak DT, Bu G, Rebeck GW. Interaction of reelin with amyloid precursor protein promotes neurite outgrowth. J Neurosci. 2009;29:7459–7473. [PMC free article] [PubMed]
  • Hoe HS, Wessner D, Beffert U, Becker AG, Matsuoka Y, Rebeck GW. F-spondin interaction with the apolipoprotein E receptor ApoEr2 affects processing of amyloid precursor protein. Molecular and cellular biology. 2005b;25:9259–9268. [PMC free article] [PubMed]
  • Beffert U, Nematollah Farsian F, Masiulis I, Hammer RE, Yoon SO, Giehl KM, Herz J. ApoE receptor 2 controls neuronal survival in the adult brain. Curr Biol. 2006;16:2446–2452. [PubMed]
  • Cheng YC, Liang CM, Chen YP, Tsai IH, Kuo CC, Liang SM. F-spondin plays a critical role in murine neuroblastoma survival by maintaining IL-6 expression. Journal of neurochemistry. 2009;110:947–955. [PubMed]
  • Chin J, Massaro CM, Palop JJ, Thwin MT, Yu GQ, Bien-Ly N, Bender A, Mucke L. Reelin depletion in the entorhinal cortex of human amyloid precursor protein transgenic mice and humans with Alzheimer's disease. J Neurosci. 2007;27:2727–2733. [PubMed]
  • Marzolo MP, Bu G. Lipoprotein receptors and cholesterol in APP trafficking and proteolytic processing, implications for Alzheimer's disease. Semin Cell Dev Biol. 2009;20:191–200. [PMC free article] [PubMed]
  • Phiel CJ, Wilson CA, Lee VM, Klein PS. GSK-3alpha regulates production of Alzheimer's disease amyloid-beta peptides. Nature. 2003;423:435–439. [PubMed]
  • De Ferrari GV, Chacon MA, Barria MI, Garrido JL, Godoy JA, Olivares G, Reyes AE, Alvarez A, Bronfman M, Inestrosa NC. Activation of Wnt signaling rescues neurodegeneration and behavioral impairments induced by beta-amyloid fibrils. Mol Psychiatry. 2003;8:195–208. [PubMed]
  • Caccamo A, Oddo S, Tran LX, LaFerla FM. Lithium reduces tau phosphorylation but not A beta or working memory deficits in a transgenic model with both plaques and tangles. The American journal of pathology. 2007;170:1669–1675. [PubMed]
  • Caricasole A, Copani A, Caraci F, Aronica E, Rozemuller AJ, Caruso A, Storto M, Gaviraghi G, Terstappen GC, Nicoletti F. Induction of Dickkopf-1, a negative modulator of the Wnt pathway, is associated with neuronal degeneration in Alzheimer's brain. J Neurosci. 2004;24:6021–6027. [PubMed]
  • Zhang QG, Wang R, Khan M, Mahesh V, Brann DW. Role of Dickkopf-1, an antagonist of the Wnt/beta-catenin signaling pathway, in estrogen-induced neuroprotection and attenuation of tau phosphorylation. J Neurosci. 2008b;28:8430–8441. [PMC free article] [PubMed]
  • De Ferrari GV, Papassotiropoulos A, Biechele T, Wavrant De-Vrieze F, Avila ME, Major MB, Myers A, Saez K, Henriquez JP, Zhao A, Wollmer MA, Nitsch RM, Hock C, Morris CM, Hardy J, Moon RT. Common genetic variation within the low-density lipoprotein receptor-related protein 6 and late-onset Alzheimer's disease. Proc Natl Acad Sci U S A. 2007;104:9434–9439. [PubMed]
  • Levi O, Michaelson DM. Environmental enrichment stimulates neurogenesis in apolipoprotein E3 and neuronal apoptosis in apolipoprotein E4 transgenic mice. J Neurochem. 2007;100:202–210. [PubMed]
  • Herz J, Chen Y. Reelin, lipoprotein receptors and synaptic plasticity. Nat Rev Neurosci. 2006;7:850–859. [PubMed]
  • Pesold C, Impagnatiello F, Pisu MG, Uzunov DP, Costa E, Guidotti A, Caruncho HJ. Reelin is preferentially expressed in neurons synthesizing gamma-aminobutyric acid in cortex and hippocampus of adult rats. Proc Natl Acad Sci U S A. 1998;95:3221–3226. [PubMed]
  • Ramos-Moreno T, Galazo MJ, Porrero C, Martinez-Cerdeno V, Clasca F. Extracellular matrix molecules and synaptic plasticity: immunomapping of intracellular and secreted Reelin in the adult rat brain. Eur J Neurosci. 2006;23:401–422. [PubMed]
  • Gong C, Wang TW, Huang HS, Parent JM. Reelin regulates neuronal progenitor migration in intact and epileptic hippocampus. J Neurosci. 2007;27:1803–1811. [PubMed]
  • Andrade N, Komnenovic V, Blake SM, Jossin Y, Howell B, Goffinet A, Schneider WJ, Nimpf J. ApoER2/VLDL receptor and Dab1 in the rostral migratory stream function in postnatal neuronal migration independently of Reelin. Proc Natl Acad Sci U S A. 2007;104:8508–8513. [PubMed]
  • Oddo S, Caccamo A, Kitazawa M, Tseng BP, LaFerla FM. Amyloid deposition precedes tangle formation in a triple transgenic model of Alzheimer's disease. Neurobiol Aging. 2003;24:1063–1070. [PubMed]
  • Santacruz K, Lewis J, Spires T, Paulson J, Kotilinek L, Ingelsson M, Guimaraes A, DeTure M, Ramsden M, McGowan E, Forster C, Yue M, Orne J, Janus C, Mariash A, Kuskowski M, Hyman B, Hutton M, Ashe KH. Tau suppression in a neurodegenerative mouse model improves memory function. Science. 2005;309:476–481. [PMC free article] [PubMed]
  • Binder LI, Guillozet-Bongaarts AL, Garcia-Sierra F, Berry RW. Tau, tangles, and Alzheimer's disease. Biochim Biophys Acta. 2005;1739:216–223. [PubMed]
  • Johnson GV, Stoothoff WH. Tau phosphorylation in neuronal cell function and dysfunction. J Cell Sci. 2004;117:5721–5729. [PubMed]
  • Frame S, Cohen P, Biondi RM. A common phosphate binding site explains the unique substrate specificity of GSK3 and its inactivation by phosphorylation. Mol Cell. 2001;7:1321–1327. [PubMed]
  • Morfini G, Szebenyi G, Elluru R, Ratner N, Brady ST. Glycogen synthase kinase 3 phosphorylates kinesin light chains and negatively regulates kinesin-based motility. Embo J. 2002;21:281–293. [PubMed]
  • Takashima A, Murayama M, Murayama O, Kohno T, Honda T, Yasutake K, Nihonmatsu N, Mercken M, Yamaguchi H, Sugihara S, Wolozin B. Presenilin 1 associates with glycogen synthase kinase-3beta and its substrate tau. Proc Natl Acad Sci U S A. 1998;95:9637–9641. [PubMed]
  • Frame S, Cohen P. GSK3 takes centre stage more than 20 years after its discovery. Biochem J. 2001;359:1–16. [PubMed]
  • Weihl CC, Ghadge GD, Kennedy SG, Hay N, Miller RJ, Roos RP. Mutant presenilin-1 induces apoptosis and downregulates Akt/PKB. J Neurosci. 1999a;19:5360–5369. [PubMed]
  • Weihl CC, Miller RJ, Roos RP. The role of beta-catenin stability in mutant PS1-associated apoptosis. Neuroreport. 1999b;10:2527–2532. [PubMed]
  • Maurer MH, Bromme JO, Feldmann RE, Jr, Jarve A, Sabouri F, Burgers HF, Schelshorn DW, Kruger C, Schneider A, Kuschinsky W. Glycogen synthase kinase 3beta (GSK3beta) regulates differentiation and proliferation in neural stem cells from the rat subventricular zone. J Proteome Res. 2007;6:1198–1208. [PubMed]
  • Noble W, Olm V, Takata K, Casey E, Mary O, Meyerson J, Gaynor K, LaFrancois J, Wang L, Kondo T, Davies P, Burns M, Veeranna, Nixon R, Dickson D, Matsuoka Y, Ahlijanian M, Lau LF, Duff K. Cdk5 is a key factor in tau aggregation and tangle formation in vivo. Neuron. 2003;38:555–565. [PubMed]
  • Wen Y, Planel E, Herman M, Figueroa HY, Wang L, Liu L, Lau LF, Yu WH, Duff KE. Interplay between cyclin-dependent kinase 5 and glycogen synthase kinase 3 beta mediated by neuregulin signaling leads to differential effects on tau phosphorylation and amyloid precursor protein processing. J Neurosci. 2008a;28:2624–2632. [PubMed]
  • Wen Y, Yu WH, Maloney B, Bailey J, Ma J, Marie I, Maurin T, Wang L, Figueroa H, Herman M, Krishnamurthy P, Liu L, Planel E, Lau LF, Lahiri DK, Duff K. Transcriptional regulation of beta-secretase by p25/cdk5 leads to enhanced amyloidogenic processing. Neuron. 2008b;57:680–690. [PMC free article] [PubMed]
  • Seki T, Arai Y. Age-related production of new granule cells in the adult dentate gyrus. Neuroreport. 1995;6:2479–2482. [PubMed]
  • Kuhn HG, Dickinson-Anson H, Gage FH. Neurogenesis in the dentate gyrus of the adult rat: age-related decrease of neuronal progenitor proliferation. The Journal of neuroscience. 1996;16:2027–2033. [PubMed]
  • Kempermann G, Kuhn HG, Gage FH. Experience-induced neurogenesis in the senescent dentate gyrus. J Neurosci. 1998;18:3206–3212. [PubMed]
  • Kempermann G, Gast D, Gage FH. Neuroplasticity in old age: sustained fivefold induction of hippocampal neurogenesis by long-term environmental enrichment. Ann Neurol. 2002;52:135–143. [PubMed]
  • Jin K, Peel AL, Mao XO, Xie L, Cottrell BA, Henshall DC, Greenberg DA. Increased hippocampal neurogenesis in Alzheimer's disease. Proc Natl Acad Sci U S A. 2004a;101:343–347. [PubMed]
  • Boekhoorn K, Joels M, Lucassen PJ. Increased proliferation reflects glial and vascular-associated changes, but not neurogenesis in the presenile Alzheimer hippocampus. Neurobiol Dis. 2006;24:1–14. [PubMed]
  • Brinton RD, Wang JM. Therapeutic potential of neurogenesis for prevention and recovery from Alzheimer's disease: allopregnanolone as a proof of concept neurogenic agent. Curr Alzheimer Res. 2006;3:185–190. [PubMed]
  • Laske C, Stellos K, Stransky E, Seizer P, Akcay O, Eschweiler GW, Leyhe T, Gawaz M. Decreased plasma and cerebrospinal fluid levels of stem cell factor in patients with early Alzheimer's disease. J Alzheimers Dis. 2008;15:451–460. [PubMed]
  • Donovan MH, Yazdani U, Norris RD, Games D, German DC, Eisch AJ. Decreased adult hippocampal neurogenesis in the PDAPP mouse model of Alzheimer's disease. J Comp Neurol. 2006;495:70–83. [PubMed]
  • Haughey NJ, Liu D, Nath A, Borchard AC, Mattson MP. Disruption of neurogenesis in the subventricular zone of adult mice, and in human cortical neuronal precursor cells in culture, by amyloid beta-peptide: implications for the pathogenesis of Alzheimer's disease. Neuromolecular Med. 2002b;1:125–135. [PubMed]
  • Thinakaran G, Teplow DB, Siman R, Greenberg B, Sisodia SS. Metabolism of the “Swedish” amyloid precursor protein variant in neuro2a (N2a) cells. Evidence that cleavage at the “beta-secretase” site occurs in the golgi apparatus. J Biol Chem. 1996;271:9390–9397. [PubMed]
  • Borchelt DR, Davis J, Fischer M, Lee MK, Slunt HH, Ratovitsky T, Regard J, Copeland NG, Jenkins NA, Sisodia SS, Price DL. A vector for expressing foreign genes in the brains and hearts of transgenic mice. Genet Anal. 1996;13:159–163. [PubMed]
  • Mirochnic S, Wolf S, Staufenbiel M, Kempermann G. Age effects on the regulation of adult hippocampal neurogenesis by physical activity and environmental enrichment in the APP23 mouse model of Alzheimer disease. Hippocampus 2009 [PubMed]
  • Jin K, Galvan V, Xie L, Mao XO, Gorostiza OF, Bredesen DE, Greenberg DA. Enhanced neurogenesis in Alzheimer's disease transgenic (PDGF-APPSw,Ind) mice. Proc Natl Acad Sci U S A. 2004b;101:13363–13367. [PubMed]
  • Lopez-Toledano MA, Shelanski ML. Increased neurogenesis in young transgenic mice overexpressing human APP(Sw, Ind) J Alzheimers Dis. 2007;12:229–240. [PubMed]
  • Gan L, Qiao S, Lan X, Chi L, Luo C, Lien L, Yan Liu Q, Liu R. Neurogenic responses to amyloid-beta plaques in the brain of Alzheimer's disease-like transgenic (pPDGF-APPSw,Ind) mice. Neurobiol Dis. 2008;29:71–80. [PMC free article] [PubMed]
  • Kolecki R, Lafauci G, Rubenstein R, Mazur-Kolecka B, Kaczmarski W, Frackowiak J. The effect of amyloidosis-beta and ageing on proliferation of neuronal progenitor cells in APP-transgenic mouse hippocampus and in culture. Acta Neuropathol 2008 [PubMed]
  • Ermini FV, Grathwohl S, Radde R, Yamaguchi M, Staufenbiel M, Palmer TD, Jucker M. Neurogenesis and alterations of neural stem cells in mouse models of cerebral amyloidosis. Am J Pathol. 2008;172:1520–1528. [PubMed]
  • Verret L, Jankowsky JL, Xu GM, Borchelt DR, Rampon C. Alzheimer's-type amyloidosis in transgenic mice impairs survival of newborn neurons derived from adult hippocampal neurogenesis. J Neurosci. 2007;27:6771–6780. [PubMed]
  • Zhang C, McNeil E, Dressler L, Siman R. Long-lasting impairment in hippocampal neurogenesis associated with amyloid deposition in a knock-in mouse model of familial Alzheimer's disease. Exp Neurol 2006 [PMC free article] [PubMed]
  • Taniuchi N, Niidome T, Goto Y, Akaike A, Kihara T, Sugimoto H. Decreased proliferation of hippocampal progenitor cells in APPswe/PS1dE9 transgenic mice. Neuroreport. 2007;18:1801–1805. [PubMed]
  • Rodriguez JJ, Jones VC, Tabuchi M, Allan SM, Knight EM, LaFerla FM, Oddo S, Verkhratsky A. Impaired adult neurogenesis in the dentate gyrus of a triple transgenic mouse model of Alzheimer's disease. PLoS ONE. 2008;3:e2935. [PMC free article] [PubMed]
  • Feng R, Rampon C, Tang YP, Shrom D, Jin J, Kyin M, Sopher B, Miller MW, Ware CB, Martin GM, Kim SH, Langdon RB, Sisodia SS, Tsien JZ. Deficient neurogenesis in forebrain-specific presenilin-1 knockout mice is associated with reduced clearance of hippocampal memory traces. Neuron. 2001;32:911–926. [PubMed]
  • Choi SH, Veeraraghavalu K, Lazarov O, Marler S, Ransohoff RM, Ramirez JM, Sisodia SS. Non-cell-autonomous effects of presenilin 1 variants on enrichment-mediated hippocampal progenitor cell proliferation and differentiation. Neuron. 2008;59:568–580. [PMC free article] [PubMed]
  • Wen PH, Hof PR, Chen X, Gluck K, Austin G, Younkin SG, Younkin LH, DeGasperi R, Gama Sosa MA, Robakis NK, Haroutunian V, Elder GA. The presenilin-1 familial Alzheimer disease mutant P117L impairs neurogenesis in the hippocampus of adult mice. Exp Neurol. 2004;188:224–237. [PubMed]
  • Wang R, Dineley KT, Sweatt JD, Zheng H. Presenilin 1 familial Alzheimer's disease mutation leads to defective associative learning and impaired adult neurogenesis. Neuroscience. 2004;126:305–312. [PubMed]
  • Chevallier NL, Soriano S, Kang DE, Masliah E, Hu G, Koo EH. Perturbed neurogenesis in the adult hippocampus associated with presenilin-1 A246E mutation. Am J Pathol. 2005;167:151–159. [PubMed]
  • Becker M, Lavie V, Solomon B. Stimulation of endogenous neurogenesis by anti-EFRH immunization in a transgenic mouse model of Alzheimer's disease. Proc Natl Acad Sci U S A. 2007;104:1691–1696. [PubMed]