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Comprehending the mechanisms underlying the pathophysiology of aging and Alzheimer’s disease has immense value for developing strategies that promote successful aging and prevent or cure Alzheimer’s disease. The first issue of the new journal, “Aging & Disease” comprises articles that discuss the current knowledge pertaining to changes in reelin signaling in normal & pathological forms of aging, memory and neurogenesis in Aging & Alzheimer’s disease, the efficacy of a non-steroidal anti-inflammatory drug aspirin in combination with docosahexaenoic acid for reducing the risk for Alzheimer’s disease, and the usefulness of stem cell transplantation for improving memory in aging and Alzheimer’s disease. The highlights and the importance of the above issues to Aging and Alzheimer’s disease are discussed in this commentary.
The world’s elderly population has increased greatly because of the rise in the mean life span. In the USA, the number of persons aged ≥65 years is supposed to grow from ~35 million in 2000 to ~70 million in 2030, and the number of persons aged ≥80 years is expected to increase from ~9.1 million in 2000 to ~18.6 million in 2030 . While the increase observed in life span generally appears pleasing, the quality of life in old age is a major issue because of the declined brain function associated with aging. Studies in elderly people imply that the hippocampus, the area of the brain important for functions such as learning, memory and mood, is highly vulnerable to normal aging and Alzheimer’s disease (AD). Brain imaging studies further suggest that decreasing brain function in the dentate gyrus (DG) of the hippocampus (an area where neurogenesis occurs all through life but declines dramatically in old age) is a main contributor to decline in memory during old age .
While some minor memory changes in older individuals are considered as a part of the normal aging process, a condition called mild cognitive impairment (MCI), characterized by impairments in memory is thought to be a transitional state between the cognition of normal aging and mild dementia . Approximately 10–15% of individuals with MCI will progress onto AD per year . At present, there is no cure for AD and other forms of dementia. Thus, advancing age is clearly a major risk factor for decline in cognitive functions and AD. Currently, AD affects ~30 million people worldwide and ~30% of people aged 85 years or older have AD . Based on one estimate, age-related dementia will affect ~4 million people per year in the coming decades resulting in AD affecting ~110 million people by the year 2050 . Therefore, comprehending the mechanisms underlying the pathophysiology of aging and AD will be critical to identify efficacious strategies that promote successful aging and prevent AD, and to develop therapies that cure age-related cognitive dysfunction and AD.
The first issue of the new journal, “Aging & Disease” comprises articles that discuss the current knowledge pertaining to changes in reelin signaling in normal & pathological forms of aging & AD , memory and neurogenesis in Aging & AD , the efficacy of a non-steroidal anti-inflammatory drug aspirin (ASA) in combination with docosahexaenoic acid (DHA) for reducing the risk for AD , and the efficiency of stem cell transplantation approach for improving memory in aging and AD . The purpose of this commentary is to highlight and discuss the significance of the above issues to Aging & AD.
The review, “Reelin-mediated Signaling during Normal and Pathological Forms of Aging”, by Doehner and Kneusel  critically discusses several important issues pertaining to the role of reelin in the developing and adult brain, which include the role of altered reelin signaling in pathological forms of aging and AD. Reelin is an important signaling protein in the developing brain where it regulates neuronal migration . The presence of reelin is also conspicuous in the gamma-amino butyric acid-ergic (GABA-ergic) interneurons of the adult brain, which implies a function for reelin as a modulator of the neurotransmission . Indeed, studies demonstrate that reelin signaling is important for synaptic plasticity in the adult brain. This is confirmed in several studies. First, a study by Weeber et al  demonstrates that mice lacking the receptors for reelin (i.e. very low density lipoprotein [VLDL] receptor or the ApoE receptor 2 [ApoER2]) display defects in contextual fear conditioning and long-term potentiation (LTP). Second, the perfusion of mouse hippocampal slices with reelin significantly enhances LTP in the CA1 subfield but such reelin-dependent augmentation of LTP is not observed in slices from VLDL receptor and ApoER2 knockout mice . Third, the heterozygote reeler mouse (HRM) shows impairments in contextual fear conditioned learning and LTP, accompanied with a pronounced impairment of hippocampal plasticity and functional inhibitory innervation , deficits in working memory function  and impaired GABA-ergic transmission . Fourth, studies show that reelin signaling pathway promotes the development of postsynaptic structures such as dendritic spines in hippocampal pyramidal neurons, implying that reelin is an important factor that promotes the maturation of target neuronal populations and the development of excitatory circuits in the postnatal hippocampus . Fifth, reelin over expression in mice enhances dendritic complexity (with enlargement of spines), synaptic contacts and LTP in newly born neurons of the DG . Sixth, the reelin gene is associated with executive function in healthy individuals .
Pertaining to aging and AD, a recent study demonstrates that age-related cognitive decline in a rat model is associated with reduced reelin expression in layer II neurons of the entorhinal cortex, in comparison to a normal reelin expression in young adult rats and aged rats with preserved cognitive function . Additional studies suggest a link between reelin dysfunction and AD neuropathology. These include the observations that: (i) polymorphisms in the reelin gene are associated with AD neuropathology [18,19]; (ii) the density reelin-expressing neurons decrease with aging ; (iii) reelin reverses the amyloid-beta (Aβ; a constituent of senile plaques in AD) oligomer induced impairments in synaptic plasticity ; (iii) abnormal glycosylation of reelin and upregulation of N-terminal fragment of reelin are seen in the cerebrospinal fluid (CSF) of AD patients ; (iv) oligomerization and aggregation of N-terminal fragments of reelin occurs in the extracellular matrix of the aged hippocampus  and co-localization of reelin with oligomeric Aβ deposits happens in aged rodents ; (v) Amyloidogenic APP processing and accelerated Aβ plaque formation takes place in transgenic AD mice with genetically reduced reelin levels . Based on the series of observations described above, Doehner and Knuesel  propose a new and interesting hypothesis that, with aging, reelin aggregates into abnormal oligomeric or protofibrillary deposits, which create a precursor condition for senile Aβ plaque formation in sporadic AD. See the article by Doehner and Knuesel in this issue for details .
The review, “Memory and Neurogenesis in Aging and Alzheimer’s disease”, by Avila and colleagues  discusses the potential relationship between the decline in hippocampal neurogenesis and the loss of memory in Aging and AD.
Aging is an important factor that substantially decreases hippocampal neurogenesis [25–28]. The fraction of neural stem cells (NSCs) that proliferate at a given time in the subgranular zone (SGZ) decreases considerably between young adult age and old age resulting in a substantially decreased production of new cells [25–27,29–31]. However, the fraction of newly born cells that differentiate into neurons does not alter between young adult age and old age in rat models [26,27,32]. Likewise, the fractions of newly born cells that exhibit long-term survival are unaltered with aging [26,27,29]. While certain parameters such as dendritic growth and acquisition of the mature neuronal marker neuron-specific nuclear antigen (NeuN) are delayed in newly born neurons of the aged hippocampus , this does not appear to interfere with the eventual integration of newly born neurons into the aged hippocampus [33,34]. Interestingly, age-related reduction in the addition of new neurons does not affect the size of granule cell layer (GCL), as a stable volume of the GCL is evident all through life [30,35], implying that aging affects the turnover of granule cells but not their number. Studies on the age-related changes in the numbers of NSCs in the hippocampal SGZ have suggested that densities of glial-fibrillary acidic protein (GFAP)-, nestin- and vimentin-expressing radial glia decrease with aging [36–39]. However, a stereological study using Sox-2 as a marker of NSCs showed that the number of Sox-2+ cells in the SGZ does not change with aging though the percentage of Sox-2+ cells expressing the proliferation marker Ki67 declines considerably with aging . Moreover, comparison of percentages of cells positive for Sox-2 & 5’-bromodeoxyuridine (BrdU) (after 4 injections of BrdU over 18 hrs) with percentages of cells positive for Sox-2 & Ki67 suggested a lengthening of the cell cycle of NSCs between young adult and old age . Thus, aging does not appear to decrease the number of NSCs in the SGZ. It is however associated with decreased numbers of proliferating NSCs, likely due to an increased quiescence of majority of NSCs with aging.
Age-related changes in NSC milieu have received significant attention pertaining to decreased neurogenesis in aging. Indeed, studies show that neurogenesis inhibitors such as the concentration of corticosteroids and glutamate are increased with aging [37,41–44]. More importantly, positive regulators of neurogenesis such as concentrations of multiple neurotrophic factors that stimulate proliferation of NSCs decline with aging [45–47]. These include fibroblast growth factor-2 (FGF-2) , insulin-like growth factor-1 (IGF-1) [46,48,49], vascular endothelial growth factor (VEGF)  and brain-derived neurotrophic factor (BDNF) [45,47]. Furthermore, reduced concentration of these factors in the aged hippocampus were associated with decreases in FGF-2+ astrocyte numbers , FGF-2 receptor density , IGF-1 receptor density [48,49], and SGZ microvasculature . Furthermore, scarcity of the above factors with aging was revealed by increased neurogenesis in the aged hippocampus with direct intracerebral administrations of FGF-2 [51,52] or IGF-1 . It is also possible that several other NSC proliferation factors such as the concentration of EGF declines with aging because, intracerebral infusions of heparin-binding epidermal-like growth factor (HB-EGF) enhanced neurogenesis in the aged hippocampus . Similarly, age-related reductions in the concentrations of gamma-amino butyric acid (GABA; indicated by reduced numbers of interneurons that synthesize GABA in the aged DG ), neuropeptide Y (NPY; denoted by declined numbers of interneurons that synthesize NPY in the aged DG ), and phosphorylated cyclic AMP response element binding protein (p-CREB; implied by a decreased expression of p-CREB in neurons of the aged DG ) likely also contribute to decreased neurogenesis in the aged hippocampus. This is because all of these factors (GABA, NPY and p-CREB) have been demonstrated to increase neurogenesis in the hippocampus [55–60]. Thus, altered NSC milieu likely underlies a greatly waned neurogenesis in old age.
The link between decreased DG neurogenesis and hippocampal-dependent cognitive impairments during aging has been a subject of intense inquiry . Although there is no universal consensus regarding this issue [62–64], a series of studies imply that decreased DG neurogenesis contributes to hippocampal-dependent cognitive deficits seen in aging. First, increased DG neurogenesis observed after exposure of middle-aged animals to an enriched environment is associated with increased capability for spatial memory . Second, aged rats with unimpaired spatial memory abilities exhibit higher levels of DG neurogenesis than aged rats with impaired spatial memory [32,66]. Third, enhanced DG neurogenesis after prolonged physical exercise in middle-aged mice is associated with better learning & memory performance . Fourth, lowering corticosterone levels in middle age enhances DG neurogenesis as well as spatial memory function . Fifth, a study using a modified version of the water maze and a transverse patterning discrimination task  demonstrated that performance in both of these tasks correlates with both hippocampal volume and neurogenesis assessed by doublecortin (DCX) immunostaining. Sixth, in aged rats with preserved spatial memory, learning enhances the survival of new cells generated before the onset of learning paradigm, suggesting the involvement of newly born neurons in the aged hippocampus in memory processing . Additionally, manipulations that decrease or selectively ablate DG neurogenesis in young adult animals lead to impairments in hippocampal-dependent learning & memory functions [69–73], and an altered DG long-term potentiation [60,74–76]. Collectively, the above studies imply that increased levels of DG neurogenesis are useful for maintaining hippocampal-dependent cognitive functions in aging.
Studies on AD brains have implied that AD is associated with increased proliferation of NSCs [77,78]. However, the differentiation of newly born cells into mature neurons appeared to be severely impaired in AD [78,79]. Studies in animal models of AD (such as in APP mice) on the other hand have documented both increased and decreased hippocampal neurogenesis [80,81]. Avila et al.  focus on these issues in their review and suggest that activation of glycogen synthase kinase 3 (GSK-3; a serine/threonine protein kinase mediating the phosphorylation of certain proteins to inhibit target proteins) underlies the decrease in net neurogenesis in both familial AD and sporadic AD, in spite of the potentially increased proliferation of NSCs in the early stage of the disease. See the article by Avila et al  in this issue for details.
The review, “Alzheimer’s disease: Fatty Acids We Eat may be Linked to a Specific Protection via Low-Dose Aspirin”, by Pomponi and colleagues  discusses the efficacy of a non-steroidal anti-inflammatory drug aspirin (ASA) in combination with docosahexaenoic acid (DHA) for reducing the risk for AD. Studies have documented that aging is associated with an increased susceptibility to an asymptomatic state of neuroinflammation characterized by activation of astrocytes and microglia, increased secretion of cytokines and nitric oxide, and leaky blood brain barrier . These changes may contribute to cognitive dysfunction in aging as well as to the development of AD . From this perspective, the idea of using non-steroidal anti-inflammatory drugs (NSAIDs) has gained importance for preventing AD. However, the results of clinical trials that tested NSAIDs on patients with AD and mild cognitive impairment (MCI) have not been supportive of this idea [83–87]. Considering these, Pomponi and colleagues  propose that NSAIDs have a preventive rather than therapeutic effect on AD and MCI and therefore they need to be administered daily prior to the onset of the symptoms of cognitive dysfunction. Furthermore, authors discuss the efficacy of aspirin (ASA), a drug recommended as an antiplatelet agent for secondary prevention in the reduction of cardiovascular events , for preventing cognitive dysfunction in aging and for decreasing the risk for developing AD. Additionally, authors suggest that coupling of low doses of ASA with omega-3 fatty acids such as DHA would lead to increased efficacy in terms of preventing the cognitive dysfunction in aging and delaying the onset of AD. The idea of co-treatment of ASA with DHA stems from several properties of DHA, which include effective neuroprotective function of DHA in the presence of ASA, association of AD with disturbed DHA metabolism [89,90], involvement of DHA in memory function, neuronal signaling, neuroprotection and the anti-inflammatory effects of DHA [91–93]. Additional reasons for concurrent administration of ASA and DHA to provide multiple levels of protection against the course of AD or dementia are described in greater detail in the article by Pomponi et al in this issue .
The review, “Stem Cell Transplantation for Enhancement of Learning and Memory in Adult Neurodegenerative Disorders”, by Waldau  discusses the efficacy of addition of new stem/progenitor cells into the hippocampus for enhancing learning and memory function in various disease models including aging and AD.
Studies have shown that providing fresh NSCs or glial restricted progenitors (GRPs) to the aging hippocampus via grafting stimulates the production of new granule cells from endogenous NSCs [94, 95]. Analyses of numbers of newly born neurons revealed increased DG neurogenesis in the aging hippocampus receiving grafts of NSCs or GRPs in comparison to both age-matched naïve hippocampus and hippocampus receiving sham-grafting surgery . As analyses of donor NSCs and GRPs revealed the presence of a variety of neurotrophic factors (which include FGF-2, BDNF, IGF-1, and VEGF) that are mitogenic to NSCs, it is likely that NSC and GRP grafts (as well as astrocytes derived from these grafts) secreted a variety of mitogenic factors that stimulated the endogenous NSCs to exhibit increased proliferation, which, in turn resulted in increased numbers of new neurons. Cells derived from NSC grafts migrated into all regions of the hippocampus including the neurogenic SGZ . In non-neurogenic regions of the hippocampus, a vast majority of graft-derived cells differentiated into glia (particularly astrocytes). However, in the neurogenic SGZ, a fraction of graft-derived cells differentiated into neurons. Another fraction remained undifferentiated which possibly represent graft-derived cells that integrated into the SGZ as NSCs. Thus, NSC grafting into the aged hippocampus is a useful approach for increasing neurogenesis. It appears that increased neurogenesis occurs via both stimulation of endogenous NSCs and addition new NSCs into the neurogenic SGZ. The review by Waldau  discusses studies that have examined the effects of NSC grafts on cognitive function in aged models. These include improvement in spatial learning and memory function after grafting of: (i) neural progenitor cells engineered to secrete the nerve growth factor ; (ii) cells derived from the hippocampal stem cell line MHP36 ; (iii) the human neural progenitor cells ; and (iv) the bone marrow stem cells . However, as none of the above studies quantified the extent of hippocampal neurogenesis, it is unknown whether functional improvements in these aged models involved increased hippocampal neurogenesis.
Several recent studies have reported improved cognitive functions (such as place recognition, spatial learning and memory or working memory function) in distinct AD models following grafting of NSCs or bone marrow stromal cells genetically engineered to secrete the nerve growth factor into the hippocampus [100–106]. The review by Waldau  critically discusses the above studies particularly the mechanisms underlying the stem cell grafting mediated functional recovery. The functional effects of stem cell grafts appeared to be mediated through increases in the hippocampal BDNF concentration in some models  where as in certain other models, co-administration of stem cells and BDNF appeared to be required for functional recovery and recovery was associated with increased numbers of nerve growth factor receptor positive neurons . Because the above studies did not quantify the extent of hippocampal neurogenesis, it remains to be addressed whether the functional improvements seen in these AD models involved increased hippocampal neurogenesis. The review by Waldau discusses various mechanisms that potentially underlie the stem cell grafting mediated cognitive improvements in aging and AD models. See the review by Waldau in this issue for details .
The author is supported by grants from the National Institute of Neurological Disorders and Stroke (RO1 NS054780 to A.K.S) and Department of Veterans Affairs (VA Merit Award to A.K.S.).