Naslov
Cholesterol accumulation upon NPC1 dysfunction alters APP expression at the cell surface leading to its increased processing through the β-secretase pathway

Autori
Malnar, Martina ; Košiček, Marko ; Hećimovicć, Silva

Vrsta, podvrsta i kategorija rada
Sažeci sa skupova, sažetak, znanstveni

Izvornik
FEBS Advanced Course: Lipid signaling and disease 2009 / - , 2009

Skup
FEBS Advanced Course: Lipid signaling and disease

Mjesto i datum
Ortona, Italija, 09.09.2009. - 15.09.2009

Vrsta sudjelovanja
Poster

Vrsta recenzije
Međunarodna recenzija

Ključne riječi
Alzheimer’s disease; amyloid-β; APP; cholesterol; β-secretase; NPC1

Sažetak
Cholesterol modulates formation of amyloid-β peptide (Aβ), a causative factor for Alzheimer’s disease (AD). Accumulation of cholesterol in late endosomal/lysosomal compartments in lysosomal storage disorder Niemann Pick type C (NPC) leads to increased A, like in AD1-3. To elucidate the mechanism of increased A upon loss of NPC1 function, we monitored APP processing between NPC model cells (NPC1-null Chinese hamster ovary (CHO)) and CHOwt cells. We observed that increased cholesterol accumulation/levels in NPC cells leads to increased formation of C99 and aggregated intracellular Aβ40. Since we determined that in vitro activities of all three secretases (-, - and -) are similar between NPC and CHOwt cells we conclude that APP cleavage through β-secretase pathway is favoured upon NPC1 dysfunction. Finding decreased APP expression at the cell surface in NPC cells, indicates that altered APP localization could cause its increased cleavage by β-secretase. We also show that increased C99/Aβ formation upon NPC1 dysfunction is dependent on increased cholesterol levels, since cholesterol depletion lowered Aβ/C99 levels in NPC cells to that as in wt cells. Cholesterol-depletion or NPC1-expression reversed APP expression at the cell surface in NPC cells, supporting that altered APP localization may be a primary cause of cholesterol-effect on APP processing upon NPC1 dysfunction. This work was supported by the Fogarty International Research Collaboration Award R03TW007335-01 and the grant of the Ministry of Science, Education and Sports, Republic of Croatia 098-0982522-2525 to S.H.

Izvorni jezik
Engleski

Znanstvena područja
Biologija, Temeljne medicinske znanosti

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