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

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.

• Authors: Mahua Maulik, Kyle Peake, JiYun Chung, Yanlin Wang, Jean E Vance, Satyabrata Kar
• Journal: Human molecular genetics (Hum Mol Genet) Vol. 24 Issue 24 Pg. 7132-50 (Dec 15 2015) ISSN: 1460-2083 [Electronic] England
• PMID: 26433932 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: [email protected].

Chemical References

• Amyloid beta-Protein Precursor
• Amyloidogenic Proteins
• Intracellular Signaling Peptides and Proteins
• Niemann-Pick C1 Protein
• Npc1 protein, mouse
• Proteins
• Cholesterol
• Proteasome Endopeptidase Complex

Topics

• Alzheimer Disease (metabolism)
• Amyloid beta-Protein Precursor (genetics, metabolism)
• Amyloidogenic Proteins (metabolism)
• Animals
• Autophagy
• Cell Line, Tumor
• Cell Survival
• Cholesterol (metabolism)
• Endosomes (metabolism)
• Humans
• Intracellular Signaling Peptides and Proteins
• Lysosomes (metabolism)
• Mice
• Mice, Inbred C57BL
• Mutation
• Neurons (metabolism)
• Niemann-Pick C1 Protein
• Proteasome Endopeptidase Complex (metabolism)
• Proteins (metabolism)