engleski

Cholesterol accumulation upon NPC1 dysfunction alters endosomal compartmentalization of β-amyloid precursor protein

Dysfunction of NPC1 protein causes Niemann Pick type C disease (NPC), a lysosomal storage disorder that is characterized by accumulation of cholesterol and glycosphingolipids in endosomal/lysosomal compartments. It has been recently demonstrated that cholesterol accumulation upon loss of NPC1 function leads to altered processing of the β-amyloid precursor protein (APP) causing increased β-amyloid peptide formation (Aβ), the causative factor of Alzheimer's disease (AD). The goal of this work was to investigate whether altered APP processing in NPC disease could be due to cholesterol-mediated trafficking defect of APP. To test this we analyzed cell surface expression, subcellular distribution and endosome compartmentalization of endogenous APP and presenilin 1 (PS1) in CHOwt and CHO NPC1-null cells. Biotinylation assay showed a marked decrease of APP at the cell surface in NPC vs. wt cells, suggesting that NPC1 loss may cause a shift in APP distribution within subcellular compartments. Indeed, subcellular and endosome fractionation confirmed that in NPC cells there is more APP and PS1 within early endosomal compartments compared to wt cells. Our results show that cholesterol accumulation upon loss of NPC1 function alters trafficking of APP/PS1 towards endosome compartments, supporting that increased localization of APP/PS1 within endocytic pathway leads to increased Aβ. This work was funded by the grants: NIH-FIRCA 1R03TW007335-01 and Ministry of Science of the Republic of Croatia 098-0982522-2525 (S.H.).

Alzheimer’s disease; APP; cholesterol; endosome; Niemann Pick type C disease; NPC1

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