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Hum Mol Genet. 2015 Dec 15;24(24):7132-50. doi: 10.1093/hmg/ddv413. Epub 2015 Oct 3.

APP overexpression in the absence of NPC1 exacerbates metabolism of amyloidogenic proteins of Alzheimer's disease.

Author information

1
Centre for Prions and Protein Folding Diseases, Centre for Neuroscience, Department of Medicine, and.
2
Department of Medicine, and.
3
Centre for Prions and Protein Folding Diseases, Department of Psychiatry, University of Alberta, Edmonton, AB T6G 2M8, Canada.
4
Centre for Prions and Protein Folding Diseases, Centre for Neuroscience, Department of Medicine, and Department of Psychiatry, University of Alberta, Edmonton, AB T6G 2M8, Canada skar@ualberta.ca.

Abstract

Amyloid-β (Aβ) peptides originating from β-amyloid precursor protein (APP) are critical in Alzheimer's disease (AD). Cellular cholesterol levels/distribution can regulate production and clearance of Aβ peptides, albeit with contradictory outcomes. To better understand the relationship between cholesterol homeostasis and APP/Aβ metabolism, we have recently generated a bigenic ANPC mouse line overexpressing mutant human APP in the absence of Niemann-Pick type C-1 protein required for intracellular cholesterol transport. Using this unique bigenic ANPC mice and complementary stable N2a cells, we have examined the functional consequences of cellular cholesterol sequestration in the endosomal-lysosomal system, a major site of Aβ production, on APP/Aβ metabolism and its relation to neuronal viability. Levels of APP C-terminal fragments (α-CTF/β-CTF) and Aβ peptides, but not APP mRNA/protein or soluble APPα/APPβ, were increased in ANPC mouse brains and N2a-ANPC cells. These changes were accompanied by reduced clearance of peptides and an increased level/activity of γ-secretase, suggesting that accumulation of APP-CTFs is due to decreased turnover, whereas increased Aβ levels may result from a combination of increased production and decreased turnover. APP-CTFs and Aβ peptides were localized primarily in early-/late-endosomes and to some extent in lysosomes/autophagosomes. Cholesterol sequestration impaired endocytic-autophagic-lysosomal, but not proteasomal, clearance of APP-CTFs/Aβ peptides. Moreover, markers of oxidative stress were increased in vulnerable brain regions of ANPC mice and enhanced β-CTF/Aβ levels increased susceptibility of N2a-ANPC cells to H2O2-induced toxicity. Collectively, our results show that cellular cholesterol sequestration plays a key role in APP/Aβ metabolism and increasing neuronal vulnerability to oxidative stress in AD-related pathology.

PMID:
26433932
PMCID:
PMC4654063
DOI:
10.1093/hmg/ddv413
[Indexed for MEDLINE]
Free PMC Article

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