β-Secretase Protein and Activity Are Increased in the Neocortex in Alzheimer Disease

Fukumoto, Hiroaki; Cheung, Bonnie; Hyman, Bradley T.; Irizarry, Michael C.

doi:10.1001/archneur.59.9.1381

Cited by 645 publications

(553 citation statements)

References 54 publications

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“…Soluble Aβ is higher in DS early in development and continues to rise with age [61]. The data presented in the current study extends these previous findings and shows that insoluble Aβ increases with age in DS but at older ages (>40 years) than that reported for soluble Aβ [61] and reaches significantly higher levels than in normal aging but closer to levels reported in AD [14,32]. We did not observe significant differences in the levels of insoluble Aβ in younger DS cases as compared to controls suggesting that insoluble Aβ reflects either an aging or a disease process.…”

Section: Discussionsupporting

confidence: 87%

“…In AD autopsy samples, BACE protein and beta-secretase activity levels are increased relative to age-matched controls [14,32,62,69] and alpha-secretase activity is reduced [62]. However, in AD brain, beta-secretase activity does not correlate with insoluble Aβ peptide [14]. The current study confirms increased beta-secretase activity with normal aging but also in DS.…”

Section: Discussionsupporting

confidence: 62%

“…In normal aging, betasecretase activity increases [15] and correlates with increased amounts of insoluble Aβ1-40 and Aβ1-42 [15]. In AD autopsy samples, BACE protein and beta-secretase activity levels are increased relative to age-matched controls [14,32,62,69] and alpha-secretase activity is reduced [62]. However, in AD brain, beta-secretase activity does not correlate with insoluble Aβ peptide [14].…”

Section: Discussionmentioning

confidence: 95%

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Alpha- and beta-secretase activity as a function of age and beta-amyloid in Down syndrome and normal brain

Nistor

Don

Parekh

et al. 2007

Neurobiology of Aging

110

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Aged individuals with Down syndrome (DS) develop Alzheimer's disease (AD) neuropathology by the age of 40 years. The purpose of the current study was to measure age-associated changes in APP processing in 36 individuals with DS (5 months-69 years) and in 26 controls (5 months-100 years). Alpha-secretase significantly decreased with age in DS, particularly in cases over the age of 40 years and was stable in controls. The levels of C-terminal fragments of APP reflecting alphasecretase processing (CTF-alpha) decreased with age in both groups. In both groups, there was significant increase in beta-secretase activity with age. CTF-beta remained constant with age in controls suggesting compensatory increases in turnover/clearance mechanisms. In DS, young individuals had the lowest CTF-beta levels that may reflect rapid conversion of beta-amyloid (Aβ) to soluble pools or efficient CTF-beta clearance mechanisms. Treatments to slow or prevent AD in the general population targeting secretase activity may be more efficacious in adults with DS if combined with approaches that enhance Aβ degradation and clearance.

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Section: Discussionsupporting

confidence: 87%

Section: Discussionsupporting

confidence: 62%

Section: Discussionmentioning

confidence: 95%

See 1 more Smart Citation

Alpha- and beta-secretase activity as a function of age and beta-amyloid in Down syndrome and normal brain

Nistor

Don

Parekh

et al. 2007

Neurobiology of Aging

110

View full text Add to dashboard Cite

show abstract

“…In addition, elevations in C99 are toxic to neurons (Neve et al , 1996), correlating with symptoms of the disease (Rockenstein et al , 2005; Tamayev et al , 2012). Importantly, we note that although much of our data were obtained using FAD models and cells from FAD patients containing mutations in presenilins, alterations in γ‐secretase activity and increased levels of C99 have been detected in sporadic AD patients as well (Fukumoto et al , 2002; Yang et al , 2003; Li et al , 2004; Pera et al , 2013). …”

Section: Discussionmentioning

confidence: 97%

Increased localization of APP‐C99 in mitochondria‐associated ER membranes causes mitochondrial dysfunction in Alzheimer disease

et al. 2017

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In the amyloidogenic pathway associated with Alzheimer disease (AD), the amyloid precursor protein (APP) is cleaved by β‐secretase to generate a 99‐aa C‐terminal fragment (C99) that is then cleaved by γ‐secretase to generate the β‐amyloid (Aβ) found in senile plaques. In previous reports, we and others have shown that γ‐secretase activity is enriched in mitochondria‐associated endoplasmic reticulum (ER) membranes (MAM) and that ER–mitochondrial connectivity and MAM function are upregulated in AD. We now show that C99, in addition to its localization in endosomes, can also be found in MAM, where it is normally processed rapidly by γ‐secretase. In cell models of AD, however, the concentration of unprocessed C99 increases in MAM regions, resulting in elevated sphingolipid turnover and an altered lipid composition of both MAM and mitochondrial membranes. In turn, this change in mitochondrial membrane composition interferes with the proper assembly and activity of mitochondrial respiratory supercomplexes, thereby likely contributing to the bioenergetic defects characteristic of AD.

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“…However, it is still unclear how the spatial and temporal patterns of APP processing correlate with the age-related profile of Aβ production and neuropathology observed in AD. Along these lines, increased regional activity of BACE1 [9], as the primary β-secretase gene, in the AD brain indicates BACE1 may play a major role in regulating the pattern of Aβ production and, ultimately, AD pathogenesis.…”

Section: Discussionmentioning

confidence: 99%

Spatial and temporal control of age-related APP processing in genomic-based β-secretase transgenic mice

Chiocco

Lamb

2007

Neurobiology of Aging

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Genetic mutations associated with Alzheimer's disease (AD) in the Amyloid Precursor Protein (APP) gene specifically alter the production of the APP processing product, amyloid-β (Aβ) peptide, generated by β-and γ-secretases. The accumulation and deposition of Aβ is hypothesized to cause AD pathogenesis, leading to the debilitating neurological deficits observed in AD patients. However, it is unclear how processing of APP to generate Aβ corresponds with the age-dependent pattern of brain-regional neurodegeneration common in AD. We have previously shown that overexpression of BACE1, the primary β-secretase gene, in mice expressing an AD mutant form of APP leads to significantly elevated regional Aβ levels, which coincide with the regional pattern of Aβ deposition. In the current study, we have used our genomic-based β-secretase transgenic mice to determine how BACE1 regulates the spatial and temporal pattern of Aβ production throughout post-natal development. Specifically, we observed unique differences in the brain-regional expression pattern between neonatal and adult BACE1 transgenic mice. These alterations in the BACE1 expression profile directly corresponds with age-related differences in regional Aβ production and deposition. These studies indicate that modulation of BACE1 expression leads to dramatic alterations in APP processing and AD-like neuropathology. Furthermore, our studies provide further evidence that BACE1 plays a major role in the regulation of the APP processing pathway, influencing the agedependent onset of AD pathogenesis.

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β-Secretase Protein and Activity Are Increased in the Neocortex in Alzheimer Disease

Abstract: The BACE protein and activity levels are increased in brain regions affected by amyloid deposition and remain increased despite significant neuronal and synaptic loss in AD.

Cited by 645 publications

References 54 publications

Alpha- and beta-secretase activity as a function of age and beta-amyloid in Down syndrome and normal brain

Alpha- and beta-secretase activity as a function of age and beta-amyloid in Down syndrome and normal brain

Increased localization of APP‐C99 in mitochondria‐associated ER membranes causes mitochondrial dysfunction in Alzheimer disease

Spatial and temporal control of age-related APP processing in genomic-based β-secretase transgenic mice

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