Effect of Ischemic Neuronal Insults on Amyloid Precursor Protein Processing

Lee, Phil Hyu; Hwang, Eun Mi; Hong, Hyun Seok; Boo, Jung Hyun; Mook‐Jung, Inhee; Huh, Kyu Ha

doi:10.1007/s11064-006-9086-y

Cited by 27 publications

(24 citation statements)

References 25 publications

(26 reference statements)

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“…Wen et al (40) found that both activity and expression of BACE1 were significantly increased in rats under transient cerebral ischemia. Another study, however, using AD transgenic mice overexpressing mutant APP showed that neither expression nor activity of BACE was significantly affected by ischemic insult; instead ADAM10 was markedly increased in the early stage of ischemic insult and then down-regulated at later stages (41). Other studies report a drastic decrease in ADAM10 and TACE protein levels with unchanged BACE1 levels in human neuroblastoma SH-SY5Y cells subjected to chronic hypoxic treatments (42)(43)(44).…”

Section: Discussionmentioning

confidence: 98%

Hypoxia-inducible Factor 1α (HIF-1α)-mediated Hypoxia Increases BACE1 Expression and β-Amyloid Generation

Zhang

Zhou

Wang

et al. 2007

Journal of Biological Chemistry

374

294

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The incidence of Alzheimer disease (AD) and vascular dementia is greatly increased following cerebral ischemia and stroke in which hypoxic conditions occur in affected brain areas. ␤-Amyloid peptide (A␤), which is derived from the ␤-amyloid precursor protein (APP) by sequential proteolytic cleavages from ␤-secretase (BACE1) and presenilin-1 (PS1)/␥-secretase, is widely believed to trigger a cascade of pathological events culminating in AD and vascular dementia. However, a direct molecular link between hypoxic insults and APP processing has yet to be established. Here, we demonstrate that acute hypoxia increases the expression and the enzymatic activity of BACE1 by up-regulating the level of BACE1 mRNA, resulting in increases in the APP C-terminal fragment-␤ (␤CTF) and A␤. Hypoxia has no effect on the level of PS1, APP, and tumor necrosis factor-␣-converting enzyme (TACE, an enzyme known to cleave APP at the ␣-secretase cleavage site). Sequence analysis, mutagenesis, and gel shift studies revealed binding of HIF-1 to the BACE1 promoter. Overexpression of HIF-1␣ increases BACE1 mRNA and protein level, whereas down-regulation of HIF-1␣ reduced the level of BACE1. Hypoxic treatment fails to further potentiate the stimulatory effect of HIF-1␣ overexpression on BACE1 expression, suggesting that hypoxic induction of BACE1 expression is primarily mediated by HIF-1␣. Finally, we observed significant reduction in BACE1 protein levels in the hippocampus and the cortex of HIF-1␣ conditional knock-out mice. Our results demonstrate an important role for hypoxia/HIF-1␣ in modulating the amyloidogenic processing of APP and provide a molecular mechanism for increased incidence of AD following cerebral ischemic and stroke injuries.An important pathologic feature of Alzheimer disease (AD) 4 is formation of extracellular senile plaques in the brain, whose major components are small peptides called ␤-amyloid (A␤) derived from ␤-amyloid precursor protein (APP). APP is sequentially cleaved first by the ␤-secretase (␤-site amyloid precursor protein cleaving enzyme, BACE) and then by the ␥-secretase complex (including presenilin, nicastrin, APH-1, and PEN-2) to generate the heterogeneous A␤ species, mostly A␤40 but also the more deleterious A␤42. Alternatively, APP can be cleaved by ␣-secretase within the A␤ domain to generate non-amyloidogenic soluble APP␣ (sAPP␣) (1-3). The exact ␣-secretase is not known, but a disintegrin and metalloprotease domain 10 (ADAM10) and TNF-␣-converting enzyme (TACE) are two likely candidates (4, 5). It is widely believed that A␤ overproduction directly or indirectly initiates a cascade of neurodegenerative steps resulting in formation of senile plaques, neurofibrillary tangles, and neuronal loss, which characterize AD (6). Hence analysis of cellular regulation affecting A␤ generation, including identification of factors regulating the level/ activity of APP cleavage enzymes, should provide invaluable information for AD therapeutic intervention.BACE is a membrane-bound aspartic protease whose activity is t...

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Section: Discussionmentioning

confidence: 98%

Hypoxia-inducible Factor 1α (HIF-1α)-mediated Hypoxia Increases BACE1 Expression and β-Amyloid Generation

Zhang

Zhou

Wang

et al. 2007

Journal of Biological Chemistry

374

294

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“…In the latter conditions, various factors such as oxidative stress (10,48,49), hypoxia (50,51), and ischemia (52) have been proposed as causes of BACE1 up-regulation, and different underlying mechanisms have been described, including the activation of hypoxia-inducible factor 1 (53), the decrease of GGA3 activity (30), and the loss of micro RNA specific clusters (32).…”

Section: Discussionmentioning

confidence: 99%

Mutant Presenilin 1 Increases the Expression and Activity of BACE1

Giliberto

Borghi

Piccini

et al. 2009

Journal of Biological Chemistry

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Mutations of the presenilin 1 (PS1) gene are the most common cause of early onset familial Alzheimer disease (FAD). PS1 mutations alter the activity of the ␥-secretase on the ␤-amyloid precursor protein (APP), leading to selective overproduction of ␤-amyloid (A␤) 42 peptides, the species that forms oligomers that may exert toxic effects on neurons. Here we show that PS1 mutations, expressed both transiently and stably, in non-neuronal and neuronal cell lines increase the expression and the activity of the ␤-secretase (BACE1), the rate-limiting step of A␤ production. Also, BACE1 expression and activity are elevated in brains of PS1 mutant knock-in mice compared with wild type littermates as well as in cerebral cortex of FAD cases bearing various PS1 mutations compared with in sporadic AD cases and controls. The up-regulation of BACE1 by PS1 mutations requires the ␥-secretase cleavage of APP and is proportional to the amount of secreted A␤42. A␤42, and not AICD (APP intracellular domain), is indeed the APP derivative that mediates the overexpression of BACE1. The effect of PS1 mutations on BACE1 may contribute to determine the wide clinical and pathological phenotype of early onset FAD.The ␤-amyloid peptide (A␤) 2 that accumulates in vulnerable brain regions in Alzheimer disease (AD) is released from the ␤-amyloid precursor protein (APP) by sequential cleavages by ␤-secretase and ␥-secretase. A single protein called BACE1 is responsible for ␤-secretase activity, whereas ␥-secretase involves at least four proteins including a catalytic subunit called presenilin-1 (PS1) (1, 2). Mutations of PS1 are the most common cause of early onset familial AD (FAD). The known effect of PS1 mutations on APP processing is the increased production of A␤ species ending at residue 42, which aggregates faster than the A␤40 isoform and accumulates in the brain in the state of soluble low molecular weight oligomers (3, 4). Small, soluble, and diffusible aggregates composed of a mixture of full-length and N-terminal-truncated A␤42 species appear early in the cerebral cortex of subjects at risk of Alzheimer disease pathology (5). The rate of accumulation as well as the properties of aggregation and toxicity of cerebral soluble A␤ depend on the ratio of the three major A␤ species, 1-42, pyroglutamate 3-42, and pyroglutamate 11-42 (6). We have shown that, in the cerebral cortex of FAD cases with mutations of PS1, the relative percentage of the two N-terminal-truncated A␤ species is significantly increased in comparison to sporadic AD cases (7). A relative increase of N-terminal-truncated A␤ peptides also occurs in the brain of transgenic mice bearing a double PS1 mutation (8). When overexpressed in cell lines, BACE1 increases the production of A␤ 11-x (9) and A␤ 3-x peptides (10) in vitro. BACE1 has been found to be transcriptionally regulated by several different mechanisms involving various transcription factors and pathways (11)(12)(13)(14)(15), and given the complexity and richness in transcription factor recognition sites of its gene p...

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“…[2][3][4][5][6] Although the underlying mechanism remains unclear, positron emission tomography scans show that patients exhibit cerebral hypometabolism many years before being diagnosed with AD. 7,8 Work in rodent models of AD indicates that severe ischemic insults, such as middle cerebral artery occlusion, increase both A␤ 9 -11 and phosphotau levels.…”

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confidence: 99%

Oligemic Hypoperfusion Differentially Affects Tau and Amyloid-β

Koike

Green

Blurton‐Jones

et al. 2010

The American Journal of Pathology

115

100

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Decreased blood flow to the brain in humans is associated with altered Alzheimer's disease (AD)-related pathology, although the underlying mechanisms by which hypoperfusion influences AD neuropathology remains unknown. To try to address this question, we developed an oligemic model of cerebral hypoperfusion in the 3xTg-AD mouse model of AD. We bilaterally and transiently occluded the common carotid artery and then examined the molecular and cellular pathways by which hypoperfusion influenced tau and amyloid-␤ proteins. We report the novel finding that a single , mild, transient hypoperfusion insult acutely increases A␤ levels by enhancing ␤-secretase protein expression. In contrast, transient hypoperfusion markedly decreases total tau levels, coincident with activation of macroautophagy and ubiquitin-proteosome pathways. Furthermore, we find that oligemia results in a significant increase specifically in tau phosphorylated at serine 212 and threonine 214 , a tau epitope associated with paired helical filaments in AD patients. Despite the mild and transient nature of this hypoperfusion injury, the pattern of decreased total tau, altered phosphorylated tau, and increased amyloid-␤ persisted for several weeks postoligemia. Our study indicates that a single, mild, cerebral hypoperfusion event produces profound and long lasting effects on both tau and amyloid-␤. This finding may have implications for the pathogenesis of AD, as it indicates for the first time that total tau and amyloid-␤ are differentially impacted by mild hypoperfusion. Alzheimer's Disease (AD), a progressive, age-related neurodegenerative disorder, currently affects more than 5.3 million people in the United States.1 Pathologically, AD is characterized by the accumulation of two hallmark brain lesions: amyloid-␤ (A␤) deposits, which can accumulate intracellularly but mainly occur as plaques composed of fibrillar aggregates of the 40-to 42-amino acid A␤ peptide, and intraneuronal neurofibrillary tangles, consisting of hyperphosphorylated and insoluble species of the microtubule-binding protein tau. The causes of sporadic AD are poorly understood, as are the factors that affect disease progression. A combination of lifestyle, environmental, dietary, and genetic and epigenetic factors, in concert with natural changes occurring in the aged brain, all likely influence the development and progression of sporadic AD. These factors can be broadly considered risk factors if they influence the initiation of disease, and co-morbidities when they influence the progression of AD.The effect of mild hypoperfusion on A␤ has been largely unstudied, however, it is known that major hypoperfusion injuries up-regulate A␤.2-6 Although the underlying mechanism remains unclear, positron emission tomography scans show that patients exhibit cerebral hypometabolism many years before being diagnosed with AD. 7,8 Work in rodent models of AD indicates that severe ischemic insults, such as middle cerebral artery occlusion, increase both A␤ 9 -11 and phosphotau levels.12-14 Althou...

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Effect of Ischemic Neuronal Insults on Amyloid Precursor Protein Processing

Cited by 27 publications

References 25 publications

Hypoxia-inducible Factor 1α (HIF-1α)-mediated Hypoxia Increases BACE1 Expression and β-Amyloid Generation

Hypoxia-inducible Factor 1α (HIF-1α)-mediated Hypoxia Increases BACE1 Expression and β-Amyloid Generation

Mutant Presenilin 1 Increases the Expression and Activity of BACE1

Oligemic Hypoperfusion Differentially Affects Tau and Amyloid-β

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