Mice deficient in BACE1, the Alzheimer's β-secretase, have normal phenotype and abolished β-amyloid generation

Luo, Yi; Bolon, Brad; Kahn, Steve; Bennett, Brian D.; Babu‐Khan, Safura; Denis, Paul; Wang, Fan; Kha, Hue T.; Zhang, Jianhua; Gong, Yunhua; Martin, Laura E.; Louis, Jean Claude; Qiao, Yan; Richards, William G.; Citron, Martin; Vassar, Robert

doi:10.1038/85059

Cited by 954 publications

(704 citation statements)

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“…Lipid droplets also accumulated in SH‐SY5Y and HeLa cells treated with DAPT alone (i.e., increasing C99), which was reversed in cells treated with DAPT+BI (i.e., preventing C99 formation) (Appendix Fig S3C). Supporting these data, and contrary to what we observed in γ‐secretase‐deficient cells but in agreement with what we saw in the DAPT+BI treated cells, MEFs in which BACE1 had been knocked out (Luo et al , 2001) were essentially devoid of LDs in the cytosol (Appendix Fig S3D). …”

Section: Resultssupporting

confidence: 91%

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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Section: Resultssupporting

confidence: 91%

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

et al. 2017

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“…Although adult animals have higher Aβ levels, CTF-β levels are markedly lower compared to neonatal animals, particularly in the cortex. These discrepancies in APP processing and Aβ metabolism are consistent with previous studies analyzing the impact of reduced Bace1 expression on APP processing [25] as well as analysis of different APP transgenic mouse models [18] and suggest that APP processing is not determined solely by the expression levels of BACE1 and APP.…”

Section: Discussionsupporting

confidence: 90%

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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“…Accordingly, there is significant interest in identifying therapeutic strategies that will lead to decreased Aβ production, and there are ongoing efforts to identify inhibitors of the enzymes that generate Aβ. 11,12 A consequence of Aβ plaque deposition in the AD brain appears to be the onset of oxidative stress, as evidenced by the generation of oxidized lipids. 13,14 These include the F2α-isoprostanes (iPF2α) that result from nonenzymatic lipid peroxidation of arachidonic acid, with elevated iPF2α levels in brain and cerebrospinal fluid of AD patients, as well as in patients with mild cognitive impairment.…”

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confidence: 99%

Brain-Penetrant Tetrahydronaphthalene Thromboxane A2-Prostanoid (TP) Receptor Antagonists as Prototype Therapeutics for Alzheimer’s Disease

Soper

Sugiyama

Herbst-Robinson

et al. 2012

ACS Chem. Neurosci.

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A hallmark pathological feature of the Alzheimer's disease (AD) brain is the presence of senile plaques, which comprise amyloid β (Aβ) peptides that are derived from the amyloid precursor protein (APP). The plaque-containing AD brain is thought to be under oxidative stress, as evidenced by increased lipid oxidation products that include isoprostane-F2αIII (iPF2αIII). IPF2αIII can bind to and activate the thromboxane A2-prostanoid (TP) receptor, and TP receptor activation causes increased Aβ production through enhancement of APP mRNA stability. Moreover, TP receptor antagonists have been shown to block iPF2αIII-induced increases of Aβ secretion. Thus, the TP receptor may be a potential drug target for AD therapy. However, here we show that existing TP receptor antagonists have poor blood-brain barrier (BBB) permeability, likely due to the presence of a carboxylic acid moiety that is believed to be important for receptor interaction, but which may hamper passive diffusion across the BBB. We now report selected analogues of a known tetrahydronaphthalene TP receptor antagonist, wherein the carboxylic acid moiety has been replaced by heterocyclic bioisosteres. These heterocyclic analogues retained relatively high affinity for the mouse and human TP receptors, and, unlike the parent carboxylic acid compound, several examples freely diffused across the BBB into the brain upon administration to mice. These results reveal that brain-penetrant tetrahydronaphthalene TP receptor antagonists can be developed by substituting the carboxylic acid moiety with a suitable nonacidic bioisostere. Compounds of this type hold promise as potential lead structures to develop drug candidates for the treatment of AD. KEYWORDS: Alzheimer's disease, amyloid precursor protein, antagonist, blood-brain barrier, plaques, thromboxane receptor A lzheimer's disease (AD) is the most common cause of dementia in elderly populations, affecting approximately 10% of individuals over age 65. 1,2 The AD brain is characterized by overt neurodegeneration 3 and the presence of senile plaques comprising insoluble fibrils of Aβ peptides which are produced through sequential proteolytic cleavage of the amyloid precursor protein (APP). 4 A second pathological hallmark of the AD brain is the occurrence of intracellular inclusions composed of hyperphosphorylated tau proteins. 5,6 Familial forms of AD can be caused by mutations in APP that result in increased proteolytic generation of amyloidogenic Aβ peptides, as well as by mutations in the presenilin proteins that are required for the proteolytic processing of APP to yield Aβ. 7−10 These genetic data provide compelling support for the "amyloid" hypothesis, which postulates that it is the production of Aβ that drives disease pathogenesis in AD. Accordingly, there is significant interest in identifying therapeutic strategies that will lead to decreased Aβ production, and there are ongoing efforts to identify inhibitors of the enzymes that generate Aβ. 11,12 A consequence of Aβ plaque deposition in the AD ...

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Mice deficient in BACE1, the Alzheimer's β-secretase, have normal phenotype and abolished β-amyloid generation

Cited by 954 publications

References 15 publications

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

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

Brain-Penetrant Tetrahydronaphthalene Thromboxane A2-Prostanoid (TP) Receptor Antagonists as Prototype Therapeutics for Alzheimer’s Disease

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