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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
 
Neurobiol Aging. Author manuscript; available in PMC 2012 November 6.
Published in final edited form as:
PMCID: PMC3490488
NIHMSID: NIHMS414212

Linking vascular disorders and Alzheimer’s disease: Potential involvement of BACE1

Abstract

The etiology of Alzheimer’s disease (AD) remains unknown. However, specific risk factors have been identified, and aging is the strongest AD risk factor. The majority of cardiovascular events occur in older people and a close relationship between vascular disorders and AD exists. Amyloid plaques, composed of the beta amyloid peptide (Aβ), are hallmark lesions in AD and evidence indicates that Aβ plays a central role in AD pathophysiology. The BACE1 enzyme is essential for Aβ generation, and BACE1 levels are elevated in AD brain. The cause(s) of this BACE1 elevation remains undetermined. Here we review the potential contribution of vascular disease to AD pathogenesis. We examine the putative vasoactive properties of Aβ and how the cellular changes associated with vascular disease may elevate BACE1 levels. Despite increasing evidence, the exact role(s) vascular disorders play in AD remains to be determined. However, given that vascular diseases can be addressed by lifestyle and pharmacologic interventions, the potential benefits of these therapies in delaying the clinical appearance and progression of AD may warrant investigation.

Keywords: Alzheimers disease, Beta amyloid peptide, BACE1, Cardiovascular, Cerebrovascular, Hypoperfusion

1. Introduction

The most prevalent forms of dementia are Alzheimer’s disease (AD) and vascular dementia (VaD; Hebert and Brayne, 1995; Pendlebury and Solomon, 1996; Erkinjuntti et al., 1999). Whereas VaD results from ischemic or hemorrhagic cerebrovascular disease, as well as from hypoperfusive ischemic cerebral injury resulting from circulatory and cardiovascular disorders (Roman et al., 1993; Roman, 2002), the etiology of AD remains elusive. While the mutations that cause the rare, familial AD (FAD) have been identified (St. George-Hyslop et al., 1990; Goate et al., 1991; Schellenberg et al., 1992; Levy-Lahad et al., 1995), the causative factors in the remaining ~95% of so-called sporadic AD cases are unknown.

Pathologically, AD is characterized by the accumulation of the beta amyloid peptide (Aβ), as fibrillar Aβ plaques and soluble oligomers in specific brain regions. Cerebrovascular pathology including cerebral amyloid angiopathy (CAA) is also frequently observed in the AD patient (reviewed in Kalaria and Ballard, 1999). In addition, intraneuronal neurofibrillary tangles composed of hyperphosphorylated tau protein, neuroinflammation, synaptic loss, neuronal dysfunction and neuronal death further characterize this disease. Studies on frontal temporal dementia with parkinsonism linked to chromosome 17 (FTDP-17; a tauopathy), in which there is an early Aβ deposition suggest that tau dysfunction could be down-stream in the pathogenic sequence (discussed in Sorrentino and Bonavita, 2007). Indeed, evidence indicates that Aβ plays an early and central role in AD pathogenesis, and the basic tenant of the amyloid hypothesis (also referred to as the Aβ cascade hypothesis; Golde et al., 2006) is that aggregates of Aβ trigger a complex pathological cascade which leads to neurodegeneration. Over time, AD brain displays increased Aβ plaque numbers and Aβ burden. Aβ is derived by endoproteolysis of the amyloid precursor protein (APP). Numerous mutations in the presenilin and APP genes are associated with increased Aβ production and cause FAD with ~100% penetrance. Aβ deposition precedes clinical symptoms of AD and Aβ is increased in the plasma of persons older than 65 years who later develop AD compared with age-matched controls. Patients with Down’s Syndrome (DS), and FAD families with a duplicated APP gene locus, exhibit total Aβ overproduction and develop early-onset AD (Rovelet-Lecrux et al., 2006). Fibrillar and oligomeric forms of Aβ appear neurotoxic both in vitro and in vivo. Importantly, in APP transgenic (Tg) mouse models of AD the genetic ablation of Aβ production is associated with the absence of neuronal loss and improved cognitive function (Ohno et al., 2004; Laird et al., 2005; Ohno et al., 2007). Such data provide direct evidence for the amyloid hypothesis in vivo, and also indicate that Aβ is directly responsible for neuronal death.

Sequential cleavage of APP in the amyloidogenic pathway by β-secretase, identified as β-site APP cleaving enzyme 1 (BACE1), and γ-secretase, a complex of presenilin 1 (PS1) or 2 (PS2), Aph1, Nicastrin and Pen2 proteins, liberates the N- and C-terminus of Aβ, respectively, thus releasing the mature Aβ peptide (reviewed in Selkoe, 2001; Vassar, 2004). BACE1 cleavage is a pre-requisite for Aβ formation, and is the initiating step in Aβ generation. Ablation of BACE1 in Tg AD models abolishes all Aβ production and prevents the subsequent development of amyloid-associated pathologies (Ohno et al., 2004, 2007; Laird et al., 2005; McConlogue et al., 2007). γ-Secretase cleavage of APP is imprecise, generating peptides of differing length. While the 40 amino acid form (Aβ40) predominates, Aβ composed of 42 amino acids (Aβ42) is the more fibrillogenic, neurotoxic entity. APP is also cleaved within the Aβ domain by α-secretase which prevents Aβ formation. Three putative α-secretase moieties have been identified: TACE (TNF-α converting enzyme), ADAM (a disintergrin and metalloprotease domain protein)-9 and ADAM-10 (Buxbaum et al., 1998; Lammich et al., 1999).

Aβ fulfills an early, critical role in AD pathogenesis. As BACE1 is critical for Aβ generation, with BACE1 deficient animals producing no Aβ at all, this enzyme represents a strong therapeutic target for AD treatment. While over-inhibition of BACE1 may cause untoward side-effects (Ohno et al., 2004, 2006; Laird et al., 2005; Willem et al., 2006; Hu et al., 2006), it has been speculated that BACE1 is a more suitable therapeutic target than either γ- or α-secretase. Pre-senilin, the catalytic member of the γ-secretase complex, is involved in the Notch signaling pathway (Levitan and Greenwald, 1995) and knocking out PS1 causes embryonic lethality (Wong et al., 1997). Although mice showing reduced PS expression and conditional neuronal knockouts are viable, they exhibit behavioral deficits (Yu et al., 2001; Dewachter et al., 2002) and they may have potential for initiating tumorogenesis (Xia et al., 2001). With regards to α-secretase, a potential treatment strategy would be to enhance the activity of this enzyme, although such an approach is perceived to be more challenging than inhibiting cleavages by the pro-amyloidogenic secretases (reviewed in Hardy, 2006).

2. Vascular disease and AD

While its etiology remains undetermined, some risk factors for sporadic AD have been identified. Aging is the major risk factor for AD, though the cause of this association remains unknown. Another strong risk factor for AD is the presence of the apolipoprotein E4 (ApoE4) allele (Corder et al., 1993), which is associated with atherosclerosis (reviewed in Mahley and Hall, 2000). Interestingly, there appears to be a close association between vascular diseases (both cardio-and cerebro-) and AD (reviewed in Kalaria and Ballard, 1999; de la Torre, 2006). While vascular disease and associated risk factors, including hypercholesterolemia, hypertension and the ApoE4 allele, correlate with elevated AD risk, the direct contribution of vascular disease to AD pathogenesis remains hotly debated. Indeed, events that cause cerebrovascular disease, including stroke or transient ischemic attacks remain exclusion criteria for AD diagnosis (Dubois et al., 2007; reviewed in Kalaria and Ballard, 1999). However, accumulating evidence makes a rigid distinction between AD and VaD no longer tenable, and it has been proposed that AD and VaD represent the extremes of a range of pathologies in which vascular and non-vascular factors co-exist to varying extents (Iadecola, 2004). Indeed, Schneider and colleagues recently reported that the most common neuropathologic finding in persons with dementia was mixed lesions, usually AD with infarcts (Schneider et al., 2007a). In addition to the fact that vascular disease and AD share common risk factors, indicative that their pathogenic mechanisms are somehow related, small ischemic lesions aggravate dementia (Snowdon et al., 1997; Riekse et al., 2004; Petrovitch et al., 2005). In fact, silent cerebral infarcts, atrial fibrillation, hypertension and angina have all been associated with a greater rate of decline in AD patients (Mielke et al., 2007; Song et al., 2007). Furthermore, AD patients exhibit more severe atherosclerosis in the cerebral arteries at the base of the brain (the circle of Willis) when compared to age-matched controls (Roher et al., 2003). Cerebral blood supply is limited by the vascular narrowing caused by these lesions (Iadecola, 2003; Beach et al., 2007). Indeed, cerebral blood flow (CBF) is reduced in the early stages of AD and the reactivity of cerebral blood vessels is impaired (reviewed in Kalaria and Ballard, 1999; Matsuda, 2001; Kalback et al., 2004). Chronic brain hypoperfusion (CBH) is a pre-clinical condition of mild cognitive impairment (MCI), a condition thought to precede AD, and is an accurate indicator for predicting AD development (Johnson et al., 1998; de la Torre, 1999; Meyer et al., 2000; Maalikjy Akkawi et al., 2005; Ruitenberg et al., 2005). Further, hypometabolism and/or hypoperfusion in temporoparietal areas, as imaged by positron emission tomography (PET; reviewed in Dubois et al., 2007), are distinctive markers of AD, and an association between impaired functionality of microvessels and unfavorable evolution of cognitive function in AD patients has been reported (Silvestrini et al., 2006).

3. Vasoactive properties of Aβ

Aβ is a key player in AD pathogenesis. While the contribution (direct vs. indirect) of vascular factors to AD pathogenesis remains to be determined, recent findings indicate that Aβ may exert vasoactive effects. The integrity of brain function relies on the balance between glucose and oxygen delivery through blood flow and the energy demands imposed by neural activity. The regulation of cerebral blood distribution to specific brain regions depending on their functional activity is known as functional hyperemia, and the neurovascular (NV) unit, composed of perivascular neurons, astrocytes, endothelial cells and vascular smooth muscle cells, plays a crucial role in this regulation. There is evidence to suggest that the NV unit undergoes dysfunction during the early stages of AD (reviewed in Kalaria and Ballard, 1999; Iadecola, 2004). In addition to depressing synaptic transmission and neuronal activity (Yu et al., 2001; Kamenetz et al., 2003; Plant et al., 2006), Aβ may also exert effects on the systemic and cerebral vasculature. Niwa and colleagues reported that Aβ has a direct effect on the vasculature in APP Tg mice (Niwa et al., 2000). Not only was resting CBF reduced in APP Tg mice, but the CBF response to somatosensory activation was reduced. Importantly, this impairment of functional hyperemia appeared prior to the appearance of amyloid in plaques and the vasculature and regional CBF was reduced as a result of soluble amyloid on eliciting vasoconstriction and attenuating endothelium-mediated vasodilation. Furthermore, superfusion of the neocortex with Aβ led to deficits in hyperemia in wild type mice and previous studies examining the effects of Aβ on isolated vessels add further support for the vascular effects of this peptide (Thomas et al., 1996; Crawford et al., 1998).

In contrast to the effects of soluble Aβ on the vasculature, Shin and colleagues very recently reported that Aβ impacts cerebrovascular function only after vascular deposition, at least in APP Tg mice (Shin et al., 2007). The reason(s) for these contrasting data remains to be determined, although as speculated by the authors, may relate to the use of different techniques to measure vascular function. As indicated previously, CAA is observed in the majority of AD brains, although whether vascular deposition is also a prerequisite for cerebrovascular dysfunction in AD patients is not known. However, CAA can lead to weakness and rupture of the vessel wall leading to hemorrhagic stroke and ischemic infarcts, both of which are known AD risk factors (Schneider et al., 2007a,b). Christie and colleagues reported that, following vasculature amyloid deposition, smooth muscle cells in the walls of pial vessels were deleteriously affected and responded inappropriately to vasodialators (Christie et al., 2001). As discussed by Coma and colleagues (Coma et al., in press), whether vascular amyloid originates from neuronal or vascular sources remains a debated topic. BACE1 is essential for Aβ generation. While BACE1 mRNA expression is not universal, it is expressed widely in human neural and non-neural cells and tissues (Sato and Kuroda, 2000), although the brain has the highest levels of BACE1 activity. With reference to cell types of the NV unit, BACE1 mRNA is highly abundant in neurons of the CNS, and is expressed at low levels in resting glial cells (Vassar et al., 1999; Marcinkiewicz and Seidah, 2000). Inflammation may enhance the glial cell expression of BACE1 (Bourne et al., 2007). In addition, vascular smooth muscle cells express all secretases involved in APP cleavage and produce Aβ, at least in vitro. Thus, Coma and colleagues propose that human cerebral smooth muscle cells may contribute to CAA observed in AD patients (Coma et al., in press).

While the above data support a causative role for Aβ in cerebrovascular dysfunction, there is accumulating evidence to indicate that Aβ accumulation also occurs as a consequence of this dysfunction. It was originally proposed that in contrast to FAD, where mutations in APP and PS genes lead to increased Aβ synthesis, the basis of increased Aβ burden over time in sporadic AD was likely due to decreased Aβ degradation and/or clearance (reviewed in Rosenberg, 2002). Indeed, dysfunction of the NV unit resulting in compromised CBF regulation and blood brain barrier transport could impair Aβ clearance and lead to increased central levels of soluble and fibrillary Aβ species. Thus, through effects on the cerebrovasculature, Aβ may autopotentiate its own elevation in the CNS and may be both the cause and the consequence of cerebrovascular impairment (Fig. 1).

Fig. 1
AD pathology and the vasculature: The effects on, and of, Aβand BACE1. Figure illustrates how specific AD risk factors might cause elevations in BACE1 and Aβ, thereby hypothetically linking these risk factors with AD pathogenesis at the ...

4. BACE1 upregulation in AD

Cleavage of APP by BACE1 is a prerequisite for Aβ formation. Tg mice deficient in BACE1 do not produce any form of Aβ, and lack the Aβ-associated pathologies, neuronal loss and memory deficits observed in age-matched Tg mice which express BACE1 (reviewed in Cole and Vassar, 2007). The homolog BACE2 shares 64% amino acid similarity with BACE1, but does not have the correct expression pattern for β-secretase (Bennett et al., 2000) and exhibits α-secretase-like activity (Yan et al., 2001; Basi et al., 2003). As reviewed elsewhere, the characteristics of BACE1 match one-to-one with the previously established properties of β-secretase activity in cells and tissues (Cole and Vassar, 2007). Table 1 summarizes the key properties of BACE1.

Table 1
The key features of BACE1: A prime therapeutic target for AD treatment (reviewed in Cole and Vassar, 2007).

The cause of Aβ elevation in AD remains unknown and it is plausible that several pathways converge to cause this elevation. The identification of BACE1 substrates (for example, voltage-gated sodium channel β-subunit Nav1β; neuregulin-1), in addition to APP, has begun to reveal potential BACE1 physiological functions (detailed below; Wang et al., 2005; Willem et al., 2006; Hu et al., 2006). Current indications are that BACE1 may function as a stress response protein that is upregulated in AD (Tamagno et al., 2002; Blasko et al., 2004; Wen et al., 2004; Tong et al., 2005; Velliquette et al., 2005; Tesco et al., 2007). Recent studies demonstrate that BACE1 levels are elevated in both AD experimental models and, importantly, in AD brain (Fukumoto et al., 2002; Holsinger et al., 2002; Tyler et al., 2002; Yang et al., 2003; Li et al., 2004; Harada et al., 2006; Zhao et al., 2007). The observed elevation in BACE1 activity is correlated with brain Aβ production in the frontal cortex (Li et al., 2004), suggesting that BACE1 elevation may lead to enhanced Aβ production and deposition. Despite normalization of BACE1 levels to synaptic markers in AD brain (Fukumoto et al., 2002), it is difficult to determine from post-mortem tissue whether a specific change is an epiphenomenon in late-stage AD, or whether it is an early event directly involved in pathogenesis. We recently addressed this issue by examining BACE1 levels in two Tg models of AD, the 5XFAD mouse (Oakley et al., 2006) that develops amyloid plaques at 2 months of age and exhibits obvious regional neuronal loss, and the Tg2576 mouse (Hsiao et al., 1996), which develops plaques later on and does not show significant neuronal death. BACE1 elevation was correlated with amyloid pathology in both models, in the absence (Tg2576) and presence (5XFAD) of significant neuronal loss (Zhao et al., 2007). Thus, BACE1 elevation appeared to be associated with amyloid pathology rather than cell death. The use of a novel, mono-specific BACE1 antibody facilitated detection of BACE1 in presynaptic neuronal structures around neuritic plaques. Taken together, our data are suggestive of a positive feedback loop, whereby Aβ42 deposits cause BACE1 levels to rise in nearby neurons through an as of yet unknown mechanism. Increased Aβ production may then ensue, initiating a vicious cycle of additional amyloid deposition followed by further elevations in BACE1 levels. Aβ42 is neurotoxic and such toxicity may induce the BACE1 increase. However, it remains unclear as to which is the initiating event, Aβ elevation and deposition or increased BACE1 activity.

5. Cellular changes associated with vascular diseases can elevate BACE1 levels and activity

Determining the causative factors in elevated BACE1 expression and activity will allow better understanding of AD pathogenesis. Individuals with AD and cerebrovascular pathologies exhibit greater cognitive impairment than those exhibiting either pathology alone (Snowdon et al., 1997; Riekse et al., 2004; Petrovitch et al., 2005; reviewed in Kalaria and Ballard, 1999). Importantly, both cardio-and cerebrovascular disease cause reduced CBF and CBH (reviewed in de la Torre, 2006). Evidence suggests that subcellular changes crucial to the development of neurodegeneration are provoked by CBH. CBH can cause hypoxia, in addition to ischemic episodes, which involves both hypoxia and reoxygenation, which cause cellular stress. Indeed, markers of oxidative stress, such as 4-hydroxy-2-nonenal (HNE) have been detected at the early pathological stages of AD (Sayre et al., 1997; Williams et al., 2006). In addition, several studies indicate that defective energy metabolism may play a fundamental role in AD pathogenesis. Post-mortem analysis of AD brain shows downregulated expression of several mitochondrial enzymes implicating brain energy metabolism impairment in AD (Rapoport, 1999; reviewed in Chandrasekaran et al., 1996). Any factor that affects normal brain function (such as AD risk factors including TBI, ischemia, hypercholesterolemia, atherosclerosis) could facilitate perturbations in energy metabolism. For example, TBI is known to cause oxidative stress (Uryu et al., 2002), and mitochondrial dysfunction is induced by the major precursors of atherosclerosis (hypercholesterolemia, hyperglycemia) and is clearly associated with atherosclerosis or cardiomyopathy in humans and animal models of oxidative stress (reviewed in Madamanchi and Runge, 2007). Indeed, young adults carrying the ApoE4 allele, and MCI patients, exhibit reduced brain glucose metabolism (Reiman et al., 1996; Small et al., 2000; Mosconi et al., 2004; Mosconi, 2005), indicating that impaired energy metabolism may be an early contributing event to AD pathology rather than a consequence of the disease process. Importantly, several key down-stream cellular consequences of vascular insults and the resulting CBH, such as hypoxia, energy depletion and cellular stress have been linked with an elevation in BACE1 levels and activity (Tamagno et al., 2002, 2005; Tong et al., 2005; Velliquette et al., 2005; Sun et al., 2006; Xiong et al., 2007; Yan et al., 2007). Thus, in addition to potential elevations in Aβ occurring as a consequence of its own vasoactive properties, as detailed above, it appears possible that cardio- and cerebrovascular insults could elevate Aβ levels via a mechanism involving BACE1 elevation. Indeed, it can be hypothesized that, in some cases, cardio- and cerebrovascular factors could initiate AD pathogenesis through BACE1 elevation (Fig. 1).

Hypoxia can facilitate AD pathogenesis (Sun et al., 2006; Zhang et al., 2007) and BACE1 mRNA expression is increased in Tg mice maintained in hypoxic conditions. Furthermore, hypoxia potentiated the memory deficit observed in these mice (Sun et al., 2006). BACE1 gene expression is tightly regulated at both the transcriptional and translational levels (reviewed in Rossner et al., 2006). The BACE1 promoter contains a number of putative binding sites for transcription factors that become activated in response to cellular stress. The hypoxia-inducible factor 1 (HIF-1) is involved in the regulation of oxygen homeostasis (Huang et al., 1999). Under conditions of low oxygen consumption, HIF-1 binds to a hypoxia-response element (HRE) in the promoter region and activates multiple genes involved in energy metabolism and cell death (Sharp and Bernaudin, 2004). The finding that the BACE1 promoter contains a functional HRE provides a molecular basis for the observed elevation of BACE1 expression during hypoxia (Sun et al., 2006; Zhang et al., 2007).

Transient hypoxic insult to cortical neurons can cause mitochondrial dysfunction. Given the apparent importance of metabolic dysfunction and amyloidosis in AD, it is noteworthy that BACE1 upregulation has been observed under various experimental conditions likely involving energy disruption and/or mitochondrial stress (Tong et al., 2005; Velliquette et al., 2005; Sun et al., 2006; Tesco et al., 2007; Xiong et al., 2007). Indeed, elevated BACE1 levels and activity have been reported in vitro (Tamagno et al., 2002, 2005; Tong et al., 2005) and in vivo (Velliquette et al., 2005; Xiong et al., 2007) under conditions of altered energy metabolism and oxidative stress.

The relationship between Aβ and oxidative stress is complex. As is the case between Aβ and changes in the vasculature, Aβ accumulation may be both the cause and the consequence of oxidative stress. While Aβ accumulation can lead to oxidative stress (Tamagno et al., 2006), oxidative stress in vitro resulted in significant increases in BACE1 promoter activity (Tong et al., 2005) and following HNE exposure, an increase in BACE1 mRNA and protein levels, together with elevated Aβ production was observed (Tamagno et al., 2002, 2005). Furthermore, the observation that oxidative stress upregulated BACE1 levels and the amyloidogenic processing of APP in smooth muscle cells led to the suggestion that this cell type may contribute to CAA observed in AD (Coma et al., in press).

The differentiation of energy inhibition from oxidative stress with regards to the pharmacological blockage of mitochondrial energetic processes in vivo is practically impossible given that inhibitors of mitochondrial respiration are generally considered to cause oxidative stress (Sherer et al., 2003; Huang et al., 2006). Following acute energy inhibition (and/or oxidative stress) in vivo, we observed a significant elevation in BACE1 protein. This long-lasting effect appeared to correspond with a significant increase in cerebral Aβ40 load. Our data indicate that translational control may be implicated in the elevation of BACE1 under conditions of energy depletion (Velliquette et al., 2005). Indeed, several studies have indicated that BACE1 may be regulated in this fashion (De Pietri Tonelli et al., 2004; Lammich et al., 2004; Rogers et al., 2004) and features of BACE1 5′ untranslated region (5′UTR) such as the GC content, the length, evolutionary conservation, and the presence of upstream AUGs, indicate that the BACE1 5′UTR may play an important role in the translational regulation of BACE1.

The observation that BACE1 levels are also elevated following traumatic brain injury (TBI; Blasko et al., 2004; Wen et al., 2004) and ischemic episodes (Wen et al., 2004; Tesco et al., 2007) adds further support for the role of BACE1 as a stress response protein. Ischemia induces apoptosis and although the contribution of programmed cell death to AD remains unclear, it is interesting that elevated BACE1 immunoreactivity was associated with a marker of apoptosis following occlusion of the middle cerebral artery (Tesco et al., 2007). Importantly, Tesco and colleagues reported that this potentiation of BACE1 was due to the post-translational stabilization of BACE1 and a significant impairment in BACE1 degradation (Tesco et al., 2007).

In addition to APP, a number of other putative BACE1 substrates have been identified, including neuregulin (NRG1; Lindholm et al., 2002; Wong et al., 2005), voltage-gated sodium channel (VGSC; Nav) subunits (Wong et al., 2005; Kim et al., 2007), lipoprotein-like receptor related protein (LRP; von Arnim et al., 2005), amyloid precursor-like proteins (APLP; Li and Sudhof, 2004; Pastorino et al., 2004), P-selectin glycoprotein ligand 1 (PSGL-1; Lichtenthaler et al., 2003) and beta-galactoside alpha 2,6-sialyltransferase (ST6Gal I; Kitazume et al., 2005). Importantly, many of these substrates may play a role in neuronal function (NRG1, VGSCβ subunits) and the cellular response to stress and/or injury, such as recovery from excitotoxicity (Aβ; Kamenetz et al., 2003), Aβ clearance (LRP; Hyman et al., 2000), synapse formation (APP, APLP1, APLP2; Herms et al., 2004; Wang et al., 2005) and immune functions (PSGL-1, ST6Gal I; Lichtenthaler et al., 2003; Kitazume et al., 2005). We speculate that following acute stress/injury BACE1 levels are elevated in order to facilitate recovery, a process that requires the cleavage of specific BACE1 substrates. However, it may be the case that chronic stress/injury may cause long-term BACE1 elevation and deleterious amyloid formation.

6. Concluding remarks

Clearly, further work is required to delineate the precise relationship between vascular disease and AD risk. However, the notion that there may be a vascular component to AD is not a new one. As detailed by Beach and colleagues (Beach et al., 2007) many early investigators believed that senile dementia and AD were caused by cerebral atherosclerosis. Following dismissal of this idea after post-mortem anatomical studies were conducted in the mid-20th century, interest in the so-called vascular hypothesis was re-ignited due to the known relationship between ApoE4 and coronary atherosclerosis and the identification of the ApoE4 allele as a strong risk factor for AD. Importantly, the study by Beach and colleagues (Beach et al., 2007) provides confirmation of a statistical association between intracranial atherosclerotic vascular disease and AD (Beach et al., 2007). While the data indicate that this association is not spurious, it remains to be determined as to whether this represents a causal or coincidental relationship.

The observations that BACE1 initiates Aβ production and that its levels are elevated in AD provide direct and compelling reasons to develop therapies directed at BACE1 inhibition to reduce Aβ and its associated toxicities. Data suggest that BACE1 levels may start building early and become sustained in the course of AD development and it is plausible that different factors cause this elevation at different stages of the disease. Our data indicate that the BACE1 elevation in AD may be actively involved in AD pathology and may occur prior to the appearance of overt neuron death (Zhao et al., 2007). However, increases in BACE1 activity have also been demonstrated in vivo occurring in response to the induction of apoptosis, an event that may be associated with the later stages of neurodegeneration (Tesco et al., 2007). We speculate that BACE1 functions as a stress response protein that is elevated under many conditions including those cellular changes evoked under conditions of cardio- and cerebrovascular disease. Indeed, there is increasing evidence to link vascular disease with AD pathogenesis and it is possible that vascular diseases may trigger AD. This may be an overly simplistic viewpoint. Admittedly, it is highly likely that sporadic AD results from multiple environmental and genetic factors that affect both Aβ production and clearance in the brain, the interaction of Aβ with other proteins implicated in AD and the susceptibility of neuronal populations to Aβ toxicity. However, given that the complications of vascular diseases can be addressed by lifestyle modifications and pharmacologic interventions, whether or not the benefits of these therapies extend to delaying the clinical appearance and progression of AD should be carefully examined.

Acknowledgments

Drs. Cole and Vassar would like to thank the many scientists involved in AD and β-secretase research whose dedicated work made this review possible. This work was supported by National Institutes of Aging Grants PO1 AG021184 and RO1 AG02260 (Dr. Vassar) and a John Douglas French Alzheimer’s Foundation Fellowship (Dr. Cole). The authors would also like to sincerely thank Mrs. Eloise Goodhew Barnett, the John Douglas French Alzheimer’s Foundation sponsor of Dr. Sarah L. Cole, for her continued support and interest in the research carried out in our laboratory.

Footnotes

Conflicts of interest

There are no actual or potential conflicts of interest.

References

  • Basi G, Frigon N, Barbour R, Doan T, Gordon G, McConlogue L, Sinha S, Zeller M. Antagonistic effects of beta-site amyloid precursor protein-cleaving enzymes 1 and 2 on beta-amyloid peptide production in cells. J Biol Chem. 2003;278:31512–31520. [PubMed]
  • Beach TG, Wilson JR, Sue LI, Newell A, Poston M, Cisneros R, Pandya Y, Esh C, Connor DJ, Sabbagh M, Walker DG, Roher AE. Circle of Willis atherosclerosis: association with Alzheimer’s disease, neuritic plaques and neurofibrillary tangles. Acta Neuropathol (Berl) 2007;113:13–21. [PubMed]
  • Bennett BD, Babu-Khan S, Loeloff R, Louis JC, Curran E, Citron M, Vassar R. Expression analysis of BACE2 in brain and peripheral tissues. J Biol Chem. 2000;275:20647–20651. [PubMed]
  • Blasko I, Beer R, Bigl M, Apelt J, Franz G, Rudzki D, Ransmayr G, Kampfl A, Schliebs R. Experimental traumatic brain injury in rats stimulates the expression, production and activity of Alzheimer’s disease beta-secretase (BACE-1) J Neural Transm. 2004;111:523–536. [PubMed]
  • Bourne KZ, Ferrari DC, Lange-Dohna C, Rossner S, Wood TG, Perez-Polo JR. Differential regulation of BACE1 promoter activity by nuclear factor-kappaB in neurons and glia upon exposure to beta-amyloid peptides. J Neurosci Res. 2007;85:1194–1204. [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]
  • Chandrasekaran Hatanpaa, Brady DR, Rapoport SI. Evidence for physiological down-regulation of brain oxidative phosphorylation in Alzheimer’s disease. Exp Neurol. 1996;142:80–88. [PubMed]
  • Christie R, Yamada M, Moskowitz M, Hyman B. Structural and functional disruption of vascular smooth muscle cells in a transgenic mouse model of amyloid angiopathy. Am J Pathol. 2001;158:1065–1071. [PubMed]
  • Cole SL, Vassar R. The Alzheimer’s disease β-secretase enzyme, BACE1. Mol Neuro. 2007;2:22. [PMC free article] [PubMed]
  • Coma M, Guix FX, Ill-Raga G, Uribesalgo I, Alameda F, Valverde MA, Munoz FJ. Oxidative stress triggers the amyloidogenic pathway in human vascular smooth muscle cells. Neurobiol Aging. 2008;29 (7):969–980. [PubMed]
  • Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC, Small GW, Roses AD, Haines JL, Pericak-Vance MA. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science. 1993;261:921–923. [PubMed]
  • Crawford F, Suo Z, Fang C, Mullan M. Characteristics of the in vitro vasoactivity of beta-amyloid peptides. Exp Neurol. 1998;150:159–168. [PubMed]
  • de la Torre JC. Critical threshold cerebral hypoperfusion causes Alzheimer’s disease? Acta Neuropathol (Berl) 1999;98:1–8. [PubMed]
  • de la Torre JC. How do heart disease and stroke become risk factors for Alzheimer’s disease? Neurol Res. 2006;28:637–644. [PubMed]
  • De Pietri Tonelli D, Mihailovich M, Di Cesare A, Codazzi F, Grohovaz F, Zacchetti D. Translational regulation of BACE-1 expression in neuronal and non-neuronal cells. Nucleic Acids Res. 2004;32:1808–1817. [PMC free article] [PubMed]
  • Dewachter I, Reverse D, Caluwaerts N, Ris L, Kuiperi C, Van den Haute C, Spittaels K, Umans L, Serneels L, Thiry E, Moechars D, Mercken M, Godaux E, Van Leuven F. Neuronal deficiency of presenilin 1 inhibits amyloid plaque formation and corrects hippocampal long-term potentiation but not a cognitive defect of amyloid precursor protein [V717I] transgenic mice. J Neurosci. 2002;22:3445–3453. [PubMed]
  • Dubois B, Feldman HH, Jacova C, Dekosky ST, Barberger-Gateau P, Cummings J, Delacourte A, Galasko D, Gauthier S, Jicha G, Meguro K, O’Brien J, Pasquier F, Robert P, Rossor M, Salloway S, Stern Y, Visser PJ, Scheltens P. Research criteria for the diagnosis of Alzheimer’s disease: revising the NINCDS-ADRDA criteria. Lancet Neurol. 2007;6:734–746. [PubMed]
  • Erkinjuntti T, Sawada T, Whitehouse PJ. The Osaka Conference on Vascular Dementia 1998. Alzheimer Dis Assoc Disord. 1999;13 (Suppl 3):S1–S3. [PubMed]
  • Fukumoto H, Cheung BS, Hyman BT, Irizarry MC. Beta-secretase protein and activity are increased in the neocortex in Alzheimer disease. Arch Neurol. 2002;59:1381–1389. [PubMed]
  • Goate A, Chartier-Harlin MC, Mullan M, Brown J, Crawford F, Fidani L, Giuffra L, Haynes A, Irving N, James L, Mant R, Newton P, Rooke K, Roques P, Talbot C, Pericak-Vance M, Roses A, Williamson R, Rossor M, Owen M, Hardy J. Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer’s disease. Nature. 1991;349:704–706. [PubMed]
  • Golde TE, Dickson D, Hutton M. Filling the gaps in the abeta cascade hypothesis of Alzheimer’s disease. Curr Alzheimer Res. 2006;3:421–430. [PubMed]
  • Harada H, Tamaoka A, Ishii K, Shoji S, Kametaka S, Kametani F, Saito Y, Murayama S. Beta-site APP cleaving enzyme 1 (BACE1) is increased in remaining neurons in Alzheimer’s disease brains. Neurosci Res. 2006;54:24–29. [PubMed]
  • Hardy J. A hundred years of Alzheimer’s disease research. Neuron. 2006;52:3–13. [PubMed]
  • Hebert R, Brayne C. Epidemiology of vascular dementia. Neuroepidemiology. 1995;14:240–257. [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]
  • Holsinger RM, McLean CA, Beyreuther K, Masters CL, Evin G. Increased expression of the amyloid precursor beta-secretase in Alzheimer’s disease. Ann Neurol. 2002;51:783–786. [PubMed]
  • Hsiao K, Chapman P, Nilsen S, Eckman C, Harigaya Y, Younkin S, Yang F, Cole G. Correlative memory deficits, Aβ elevation, and amyloid plaques in transgenic mice. Science. 1996;274:99–103. [PubMed]
  • Hu X, Hicks CW, He W, Wong P, Macklin WB, Trapp BD, Yan R. Bace1 modulates myelination in the central and peripheral nervous system. Nat Neurosci. 2006;9:1520–1525. [PubMed]
  • Huang LE, Willmore WG, Gu J, Goldberg MA, Bunn HF. Inhibition of hypoxia-inducible factor 1 activation by carbon monoxide and nitric oxide. Implications for oxygen sensing and signalling. J Biol Chem. 1999;274:9038–9044. [PubMed]
  • Huang LS, Sun G, Cobessi D, Wang AC, Shen JT, Tung EY, Anderson VE, Berry EA. 3-nitropropionic acid is a suicide inhibitor of mitochondrial respiration that, upon oxidative by complex II, forms a covalent adduct with a catalytic base arginine in the active site of the enzyme. J Biol Chem. 2006;281:5965–5972. [PMC free article] [PubMed]
  • Hyman BT, Strickland D, Rebeck GW. Role of the low-density lipoprotein receptor-related protein in beta-amyloid metabolism and Alzheimer disease. Arch Neurol. 2000;57:646–650. [PubMed]
  • Iadecola C. Atherosclerosis and neurodegeneration: unexpected conspirators in Alzheimer’s dementia. Arterioscler Thromb Vasc Biol. 2003;23:1951–1953. [PubMed]
  • Iadecola C. Neurovascular regulation in the normal brain and in Alzheimer’s disease. Nat Rev Neurosci. 2004;5:347–360. [PubMed]
  • Johnson KA, Jones K, Holman BL, Becker JA, Spiers PA, Satlin A, Albert MS. Preclinical prediction of Alzheimer’s disease using SPECT. Neurology. 1998;50:1563–1571. [PubMed]
  • Kalaria RN, Ballard C. Overlap between pathology of Alzheimer disease and vascular dementia. Alzheimer Dis Assoc Disord. 1999;13 (Suppl 3):S115–S123. [PubMed]
  • Kalback W, Esh C, Castano EM, Rahman A, Kokjohn T, Luehrs DC, Sue L, Cisneros R, Gerber F, Richardson C, Bohrmann B, Walker DG, Beach TG, Roher AE. Atherosclerosis, vascular amyloidosis and brain hypoperfusion in the pathogenesis of sporadic Alzheimer’s disease. Neurol Res. 2004;26:525–539. [PubMed]
  • Kamenetz F, Tomita T, Hsieh H, Seabrook G, Borchelt D, Iwatsubo T, Sisodia S, Malinow R. APP processing and synaptic function. Neuron. 2003;37:925–937. [PubMed]
  • Kim DY, Carey BW, Wang H, Ingano LA, Binshtok AM, Wertz MH, Pettingell WH, He P, Lee VM, Woolf CJ, Kovacs DM. BACE1 regulates voltage-gated sodium channels and neuronal activity. Nat Cell Biol. 2007;9:755–764. [PMC free article] [PubMed]
  • Kitazume S, Nakagawa K, Oka R, Tachida Y, Ogawa K, Luo Y, Citron M, Shitara H, Taya C, Yonekawa H, Paulson JC, Miyoshi E, Taniguchi N, Hashimoto Y. In vivo cleavage of alpha2,6-sialyltransferase by Alzheimer beta-secretase. J Biol Chem. 2005;280:8589–8595. [PubMed]
  • Laird FM, Cai H, Savonenko AV, Farah MH, He K, Melnikova T, Wen H, Chiang HC, Xu G, Koliatsos VE, Borchelt DR, Price DL, Lee HK, Wong PC. BACE1, a major determinant of selective vulnerability of the brain to amyloid-beta amyloidogenesis, is essential for cognitive, emotional, and synaptic functions. J Neurosci. 2005;25:11693–11709. [PMC free article] [PubMed]
  • Lammich S, Schobel S, Zimmer AK, Lichtenthaler SF, Haass C. Expression of the Alzheimer protease BACE1 is suppressed via its 5′-untranslated region. EMBO Rep. 2004;5:620–625. [PubMed]
  • Lammich S, Kojro E, Postina R, Gilbert S, Pfeiffer R, Jasionowski M, Haass C, Fahrenholz F. Constitutive and regulated alpha-secretase cleavage of Alzheimer’s amyloid precursor protein by a disintegrin metalloprotease. Proc Natl Acad Sci USA. 1999;96:3922–3927. [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]
  • Levy-Lahad E, Wasco W, Poorkaj P, Romano DM, Oshima J, Pettingell WH, Yu CE, Jondro PD, Schmidt SD, Wang K, Crowley AC, Fu YH, Guenette SY, Galas D, Nemens E, Wijsman EM, Bird TD, Schellenberg GD, Tanzi RE. Candidate gene for the chromosome 1 familial Alzheimer’s disease locus. Science. 1995;269:973–977. [PubMed]
  • Li Q, Sudhof TC. Cleavage of amyloid-beta precursor protein and amyloid-beta precursor-like protein by BACE 1. J Biol Chem. 2004;279:10542–10550. [PubMed]
  • Li R, Lindholm K, Yang LB, Yue X, Citron M, Yan R, Beach T, Sue L, Sabbagh M, Cai H, Wong P, Price D, Shen Y. Amyloid beta peptide load is correlated with increased beta-secretase activity in sporadic Alzheimer’s disease patients. Proc Natl Acad Sci USA. 2004;101:3632–3637. [PubMed]
  • Lichtenthaler SF, Dominguez DI, Westmeyer GG, Reiss K, Haass C, Saftig P, De Strooper B, Seed B. The cell adhesion protein P-selectin glycoprotein ligand-1 is a substrate for the aspartyl protease BACE1. J Biol Chem. 2003;278:48713–48719. [PubMed]
  • Lindholm T, Cullheim S, Deckner M, Carlstedt T, Risling M. Expression of neuregulin and ErbB3 and ErbB4 after a traumatic lesion in the ventral funiculus of the spinal cord and in the intact primary olfactory system. Exp Brain Res. 2002;142:81–90. [PubMed]
  • Maalikjy Akkawi N, Borroni B, Agosti C, Magoni M, Broli M, Pezzini A, Padovani A. Volume cerebral blood flow reduction in pre-clinical stage of Alzheimer disease: evidence from an ultrasonographic study. J Neurol. 2005;252:559–563. [PubMed]
  • Madamanchi NR, Runge MS. Mitochondrial dysfunction in atherosclerosis. Circ Res. 2007;100:460–473. [PubMed]
  • Mahley RW, Hall SC. Apolipoprotein E: far more than a lipid transport protein. Annu Rev Genomics Hum Genet. 2000;01:507–537. [PubMed]
  • Marcinkiewicz M, Seidah NG. Coordinated expression of β-amyloid precursor protein and the putative β-secretase BACE and α-secretase ADAM10 in mouse and human brain. J Neurochem. 2000;75:2133–2143. [PubMed]
  • Matsuda H. Cerebral blood flow and metabolic abnormalities in Alzheimer’s disease. Ann Nucl Med. 2001;15:85–92. [PubMed]
  • McConlogue L, Buttini M, Anderson JP, Brigham EF, Chen KS, Freedman SB, Games D, Johnson-Wood K, Lee M, Zeller M, Liu W, Motter R, Sinha S. Partial reduction of BACE1 has dramatic effects on Alzheimer plaque and synaptic pathology in APP transgenic mice. J Biol Chem. 2007;282:26326–26334. [PubMed]
  • Meyer JS, Rauch G, Rauch RA, Haque A. Risk factors for cerebral hypoperfusion, mild cognitive impairment, and dementia. Neurobiol Aging. 2000;21:161–169. [PubMed]
  • Mielke MM, Rosenberg PB, Tschanz J, Cook L, Corcoran C, Hayden KM, Norton M, Rabins PV, Green RC, Welsh-Bohmer KA, Breitner JC, Munger R, Lyketsos CG. Vascular factors predict rate of progression in Alzheimer disease. Neurology. 2007;69:1850–1858. [PubMed]
  • Mosconi L. Brain glucose metabolism in the early and specific diagnosis of Alzheimer’s disease. FDG-PET studies in MCI and AD. Eur J Nucl Med Mol Imaging. 2005;32:486–510. [PubMed]
  • Mosconi L, Perani D, Sorbi S, Herholz K, Nacmias B, Holthoff V, Salmon E, Baron JC, De Cristofaro MT, Padovani A, Borroni B, Franceschi M, Bracco L, Pupi A. MCI conversion to dementia and the APOE genotype: a prediction study with FDG-PET. Neurology. 2004;63:2332–2340. [PubMed]
  • Niwa K, Younkin L, Ebeling C, Turner SK, Westaway D, Younkin S, Ashe KH, Carlson GA, Iadecola C. Abeta 1-40-related reduction in functional hyperemia in mouse neocortex during somatosensory activation. Proc Natl Acad Sci USA. 2000;97:9735–9740. [PubMed]
  • Oakley H, Cole SL, Logan S, Maus E, Shao P, Craft J, Guillozet-Bongaarts A, Ohno M, Disterhoft J, Van Eldik L, Berry R, Vassar R. Intraneuronal beta-amyloid aggregates, neurodegeneration, and neuron loss in transgenic mice with five familial Alzheimer’s disease mutations: potential factors in amyloid plaque formation. J Neurosci. 2006;26:10129–10140. [PubMed]
  • Ohno M, Chang L, Tseng W, Oakley H, Citron M, Klein WL, Vassar R, Disterhoft JF. Temporal memory deficits in Alzheimer’s mouse models: rescue by genetic deletion of BACE1. Eur J Neurosci. 2006;23:251–260. [PubMed]
  • Ohno M, Cole SL, Yasvoina M, Zhao J, Citron M, Berry R, Disterhoft JF, Vassar R. BACE1 gene deletion prevents neuron loss and memory deficits in 5XFAD APP/PS1 transgenic mice. Neurobiol Dis. 2007;26:134–145. [PMC free article] [PubMed]
  • Ohno M, Sametsky EA, Younkin LH, Oakley H, Younkin SG, Citron M, Vassar R, Disterhoft JF. BACE1 deficiency rescues memory deficits and cholinergic dysfunction in a Mouse Model of Alzheimer’s Disease. Neuron. 2004;41:27–33. [PubMed]
  • Pastorino L, Ikin AF, Lamprianou S, Vacaresse N, Revelli JP, Platt K, Paganetti P, Mathews PM, Harroch S, Buxbaum JD. BACE (beta-secretase) modulates the processing of APLP2 in vivo. Mol Cell Neurosci. 2004;25:642–649. [PubMed]
  • Pendlebury WW, Solomon PR. Alzheimer’s disease. Clin Symp. 1996;48:2–32. [PubMed]
  • Petrovitch H, Ross GW, Steinhorn SC, Abbott RD, Markesbery W, Davis D, Nelson J, Hardman J, Masaki K, Vogt MR, Launer L, White LR. AD lesions and infarcts in demented and non-demented Japanese-American men. Ann Neurol. 2005;57:98–103. [PubMed]
  • Plant LD, Webster NJ, Boyle JP, Ramsden M, Freir DB, Peers C, Pearson HA. Amyloid beta peptide as a physiological modulator of neuronal ‘A’-type K+ current. Neurobiol Aging. 2006;27:1673–1683. [PubMed]
  • Rapoport SI. In vivo PET imaging and postmortem studies suggest potentially reversible and irreversible stages of brain metabolic failure in Alzheimer’s disease. Eur Arch Psychiatry Clin Neurosci. 1999;249 (Suppl 3):46–55. [PubMed]
  • Reiman EM, Caselli RJ, Yun LS, Chen K, Bandy D, Minoshima S, Thibodeau SN, Osborne D. Preclinical evidence of Alzheimer’s disease in persons homozygous for the epsilon 4 allele for apolipoprotein E. N Engl J Med. 1996;334:752–758. [PubMed]
  • Riekse RG, Leverenz JB, McCormick W, Bowen JD, Teri L, Nochlin D, Simpson K, Eugenio C, Larson EB, Tsuang D. Effect of vascular lesions on cognition in Alzheimer’s disease: a community-based study. J Am Geriatr Soc. 2004;52:1442–1448. [PMC free article] [PubMed]
  • Rogers GW, Edelman GM, Jr, Mauro VP. Differential utilization of upstream AUGs in the beta-secretase mRNA suggests that a shunting mechanism regulates translation. Proc Natl Acad Sci USA. 2004;101:2794–2799. [PubMed]
  • Roher AE, Esh C, Kokjohn TA, Kalback W, Luehrs DC, Seward JD, Sue LI, Beach TG. Circle of willis atherosclerosis is a risk factor for sporadic Alzheimer’s disease. Arterioscler Thromb Vasc Biol. 2003;23:2055–2062. [PubMed]
  • Roman GC. Vascular dementia revisited: diagnosis, pathogenesis, treatment, and prevention. Med Clin North Am. 2002;86:477–499. [PubMed]
  • Roman GC, Tatemichi TK, Erkinjuntti T, Cummings JL, Masdeu JC, Garcia JH, Amaducci L, Orgogozo JM, Brun A, Hofman A, Moody DM, O’Brien MD, Yamaguchi T, Grafman J, Drayer BP, Bennett DA, Fisher M, Ogata J, Kokmen E, Bermejo F, Wolf PA, Gorelick PB, Bick KL, Pajeau AK, Bell MA, DeCarli C, Culebras A, Korczyn AD, Bogousslavsky J, Hartmann A, Scheinberg P. Vascular dementia: diagnostic criteria for research studies. Report of the NINDS-AIREN International Workshop. Neurology. 1993;43:250–260. [PubMed]
  • Rosenberg RN. Explaining the cause of the amyloid burden in Alzheimer disease. Arch Neurol. 2002;59:1367–1368. [PubMed]
  • Rossner S, Sastre M, Bourne K, Lichtenthaler SF. Transcriptional and translational regulation of BACE1 expression—implications for Alzheimer’s disease. Prog Neurobiol. 2006;79:95–111. [PubMed]
  • Rovelet-Lecrux A, Hannequin D, Raux G, Le Meur N, Laquerriere A, Vital A, Dumanchin C, Feuillette S, Brice A, Vercelletto M, Dubas F, Frebourg T, Campion D. APP locus duplication causes autosomal dominant early-onset Alzheimer disease with cerebral amyloid angiopathy. Nat Genet. 2006;38:24–26. [PubMed]
  • Ruitenberg A, den Heijer T, Bakker SL, van Swieten JC, Koudstaal PJ, Hofman A, Breteler MM. Cerebral hypoperfusion and clinical onset of dementia: the Rotterdam Study. Ann Neurol. 2005;57:789–794. [PubMed]
  • Sato JI, Kuroda Y. Amyloid precursor protein β-secretase (BACE) mRNA expression in human neural cell lines following induction of neuronal differentiation and exposure to cytokines and growth factors. Neuropathology. 2000;20:289–296. [PubMed]
  • Sayre LM, Zelasko DA, Harris PL, Perry G, Salomon RG, Smith MA. 4-Hydroxynonenal-derived advanced lipid peroxidation end products are increased in Alzheimer’s disease. J Neurochem. 1997;68:2092–2097. [PubMed]
  • Schellenberg GD, Bird TD, Wijsman EM, Orr HT, Anderson L, Nemens E, White JA, Bonnycastle L, Weber JL, Alonso ME, Potter H, Heston LH, Martin GM. Genetic linkage evidence for a familial Alzheimer’s disease locus on chromosome 14. Science. 1992;258:668–671. [PubMed]
  • Schneider JA, Arvanitakis Z, Bang W, Bennett DA. Mixed brain pathologies account for most dementia cases in community-dwelling older persons. Neurology. 2007a;69:2197–2204. [PubMed]
  • Schneider JA, Boyle PA, Arvanitakis Z, Bienias JL, Bennett DA. Subcortical infarcts, Alzheimer’s disease pathology, and memory function in older persons. Ann Neurol. 2007b;62:59–66. [PubMed]
  • Selkoe DJ. Alzheimer’s disease: genes, proteins, and therapy. Physiol Rev. 2001;81:741–766. [PubMed]
  • Sharp FR, Bernaudin M. HIF1 and oxygen sensing in the brain. Nat Rev Neurosci. 2004;5:437–448. [PubMed]
  • Sherer TB, Betarbet R, Testa CM, Seo BB, Richardson JR, Kim JH, Miller GW, Yagi T, Matsuno-Yagi A, Greenamyre JT. Mechanism of toxicity in rotenone models of Parkinson’s disease. J Neurosci. 2003;23:10756–10764. [PubMed]
  • Shin HK, Jones PB, Garcia-Alloza M, Borrelli L, Greenberg SM, Bacskai BJ, Frosch MP, Hyman BT, Moskowitz MA, Ayata C. Age-dependent cerebrovascular dysfunction in a transgenic mouse model of cerebral amyloid angiopathy. Brain. 2007;130:2310–2319. [PubMed]
  • Silvestrini M, Pasqualetti P, Baruffaldi R, Bartolini M, Handouk Y, Matteis M, Moffa F, Provinciali L, Vernieri F. Cerebrovascular reactivity and cognitive decline in patients with Alzheimer disease. Stroke. 2006;37:1010–1015. [PubMed]
  • Small GW, Ercoli LM, Silverman DH, Huang SC, Komo S, Bookheimer SY, Lavretsky H, Miller K, Siddarth P, Rasgon NL, Mazziotta JC, Saxena S, Wu HM, Mega MS, Cummings JL, Saunders AM, Pericak-Vance MA, Roses AD, Barrio JR, Phelps ME. Cerebral metabolic and cognitive decline in persons at genetic risk for Alzheimer’s disease. Proc Natl Acad Sci USA. 2000;97:6037–6042. [PubMed]
  • Snowdon DA, Greiner LH, Mortimer JA, Riley KP, Greiner PA, Markesbery WR. Brain infarction and the clinical expression of Alzheimer disease. The Nun Study Jama. 1997;277:813–817. [PubMed]
  • Sorrentino G, Bonavita V. Neurondegeneration and Alzheimer’s disease: the lesson from tauopathies. Neurol Sci. 2007;28:63–71. [PubMed]
  • Song IU, Kim JS, Kim YI, Eah KY, Lee KS. Clinical significance of silent cerebral infarctions in patients with Alzheimer disease. Cogn Behav Neurol. 2007;20:93–98. [PubMed]
  • St George-Hyslop PH, Haines JL, Farrer LA, Polinsky R, Van Broeckhoven C, Goate A, Crapper McLachlan DR, Orr H, Bruni AC, Sorbi S, Rainero I, Foncin JF, Pollen D, Cantu JM, Tupler R, Voskresenskaya N, Mayeux R, Growdon J, Fried VA, Myers RH, Nee L, Backhovens H, Martin JJ, Rossor M, Owen MJ, Mullan M, Percy ME, Karlinsky H, Rich S, Heston L, Montesi M, Mortilla M, Nacmias N, Gusella JF, Hardy JA. Genetic linkage studies suggest that Alzheimer’s disease is not a single homogeneous disorder. Nature. 1990;347:194–197. [PubMed]
  • Sun X, He G, Qing H, Zhou W, Dobie F, Cai F, Staufenbiel M, Huang LE, Song W. Hypoxia facilitates Alzheimer’s disease pathogenesis by up-regulating BACE1 gene expression. Proc Natl Acad Sci USA. 2006;103:18727–18732. [PubMed]
  • Tamagno E, Bardini P, Guglielmotto M, Danni O, Tabaton M. The various aggregation states of beta-amyloid 1-42 mediate different effects on oxidative stress, neurodegeneration, and BACE-1 expression. Free Radic Biol Med. 2006;41:202–212. [PubMed]
  • Tamagno E, Bardini P, Obbili A, Vitali A, Borghi R, Zaccheo D, Pronzato MA, Danni O, Smith MA, Perry G, Tabaton M. Oxidative stress increases expression and activity of BACE in NT2 neurons. Neurobiol Dis. 2002;10:279–288. [PubMed]
  • Tamagno E, Parola M, Bardini P, Piccini A, Borghi R, Guglielmotto M, Santoro G, Davit A, Danni O, Smith MA, Perry G, Tabaton M. Beta-site APP cleaving enzyme up-regulation induced by 4-hydroxynonenal is mediated by stress-activated protein kinases pathways. J Neurochem. 2005;92:628–636. [PubMed]
  • Tesco G, Koh YH, Kang EL, Cameron AN, Das S, Sena-Esteves M, Hiltunen M, Yang SH, Zhong Z, Shen Y, Simpkins JW, Tanzi RE. Depletion of GGA3 stabilizes BACE and enhances beta-secretase activity. Neuron. 2007;54:721–737. [PMC free article] [PubMed]
  • Thomas T, Thomas G, McLendon C, Sutton T, Mullan M. beta-Amyloid-mediated vasoactivity and vascular endothelial damage. Nature. 1996;380:168–171. [PubMed]
  • Tong Y, Zhou W, Fung V, Christensen MA, Qing H, Sun X, Song W. Oxidative stress potentiates BACE1 gene expression and Abeta generation. J Neural Transm. 2005;112:455–469. [PubMed]
  • Tyler SJ, Dawbarn D, Wilcock GK, Allen SJ. alpha- and beta-secretase: profound changes in Alzheimer’s disease. Biochem Biophys Res Commun. 2002;299:373–376. [PubMed]
  • Uryu K, Laurer H, McIntosh T, Pratico D, Martinez D, Leight S, Lee VM, Trojanowski JQ. Repetitive mild brain trauma accelerates Abeta deposition, lipid peroxidation, and cognitive impairment in a transgenic mouse model of Alzheimer amyloidosis. J Neurosci. 2002;22:446–454. [PubMed]
  • Vassar R. BACE1: the beta-secretase enzyme in Alzheimer’s disease. J Mol Neurosci. 2004;23:105–114. [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]
  • Velliquette RA, O’Connor T, Vassar R. Energy inhibition elevates beta-secretase levels and activity and is potentially amyloidogenic in APP transgenic mice: possible early events in Alzheimer’s disease pathogenesis. J Neurosci. 2005;25:10874–10883. [PubMed]
  • von Arnim CA, Kinoshita A, Peltan ID, Tangredi MM, Herl L, Lee BM, Spoelgen R, Hshieh TT, Ranganathan S, Battey FD, Liu CX, Bacskai BJ, Sever S, Irizarry MC, Strickland DK, Hyman BT. The low density lipoprotein receptor-related protein (LRP) is a novel beta-secretase (BACE1) substrate. J Biol Chem. 2005;280:17777–17785. [PubMed]
  • Wang P, Yang G, Mosier DR, Chang P, Zaidi T, Gong YD, Zhao NM, Dominguez B, Lee KF, Gan WB, Zheng H. Defective neuromuscular synapses in mice lacking amyloid precursor protein (APP) and APP-Like protein 2. J Neurosci. 2005;25:1219–1225. [PubMed]
  • Wen Y, Onyewuchi O, Yang S, Liu R, Simpkins JW. Increased beta-secretase activity and expression in rats following transient cerebral ischemia. Brain Res. 2004;1009:1–8. [PubMed]
  • Willem M, Garratt AN, Novak B, Citron M, Kaufmann S, Rittger A, DeStrooper B, Saftig P, Birchmeier C, Haass C. Control of peripheral nerve myelination by the beta-secretase BACE1. Science. 2006;314:664–666. [PubMed]
  • Williams TI, Lynn BC, Markesbery WR, Lovell MA. Increased levels of 4-hydroxynonenal and acrolein, neurotoxic markers of lipid peroxidation, in the brain in Mild Cognitive Impairment and early Alzheimer’s disease. Neurobiol Aging. 2006;27:1094–1099. [PubMed]
  • Wong HK, Sakurai T, Oyama F, Kaneko K, Wada K, Miyazaki H, Kurosawa M, De Strooper B, Saftig P, Nukina N. Beta subunits of voltage-gated sodium channels are novel substrates of beta-site amyloid precursor protein-cleaving enzyme (BACE1) and gamma-secretase. J Biol Chem. 2005;280:23009–23017. [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]
  • 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 USA. 2001;98:10863–10868. [PubMed]
  • Xiong K, Cai H, Luo XG, Struble RG, Clough RW, Yan XX. Mitochondrial respiratory inhibition and oxidative stress elevate beta-secretase (BACE1) proteins and activity in vivo in the rat retina. Exp Brain Res. 2007;181:435–446. [PubMed]
  • Yan R, Munzner JB, Shuck ME, Bienkowski MJ. BACE2 functions as an alternative alpha-secretase in cells. J Biol Chem. 2001;276:34019–34027. [PubMed]
  • Yan XX, Xiong K, Luo XG, Struble RG, Clough RW. Beta-secretase expression in normal and functionally deprived rat olfactory bulbs: inverse correlation with oxidative metabolic activity. J Comp Neurol. 2007;501:52–69. [PubMed]
  • Yang LB, Lindholm K, Yan R, Citron M, Xia W, Yang XL, Beach T, Sue L, Wong P, Price D, Li R, Shen Y. Elevated beta-secretase expression and enzymatic activity detected in sporadic Alzheimer disease. Nat Med. 2003;9:3–4. [PubMed]
  • Yu H, Saura CA, Choi SY, Sun LD, Yang X, Handler M, Kawarabayashi T, Younkin L, Fedeles B, Wilson MA, Younkin S, Kandel ER, Kirkwood A, Shen J. APP processing and synaptic plasticity in presenilin-1 conditional knockout mice. Neuron. 2001;31:713–726. [PubMed]
  • Zhang X, Zhou K, Wang R, Cui J, Lipton SA, Liao FF, Xu H, Zhang YW. Hypoxia-inducible factor 1alpha (HIF-1alpha)-mediated hypoxia increases BACE1 expression and beta-amyloid generation. J Biol Chem. 2007;282:10873–10880. [PubMed]
  • Zhao J, Fu Y, Yasvoina M, Shao P, Hitt B, O’Connor T, Logan S, Maus E, Citron M, Berry R, Binder L, Vassar R. Beta-site amyloid precursor protein cleaving enzyme 1 levels become elevated in neurons around amyloid plaques: implications for Alzheimer’s disease pathogenesis. J Neurosci. 2007;27:3639–3649. [PubMed]