Effect of cholesterol accumulation on the metabolism of APLP1 and APLP2 proteins in CHO NPC1-/- cells

Kular, Dolores (2011) Effect of cholesterol accumulation on the metabolism of APLP1 and APLP2 proteins in CHO NPC1-/- cells. Diploma thesis, Faculty of Science > Department of Biology.

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Abstract

Altered metabolism of amyloid precursor protein (APP) leading to increased formation of amyloid-β peptide (Aβ) is the central event in the pathogenesis of Alzheimer's disease (AD). Previous studies have shown that accumulation of cholesterol in cells affects the processing of APP protein and generates increased levels of Aβ peptide and increased levels of APP C-terminal fragments (APP-CTFs). Similar pathophysiology was observed in a rare hereditary disease of cholesterol accumulation, Niemann-Pick type C (NPC), and this disease proved to be a good model to study the mechanism(s) of cholesterol action on the development of AD. Our recent results have shown that cholesterol accumulation in NPC disease favours APP processing by β-secretase probably due to decreased expression of APP at the cell surface and its increased partitioning to cholesterol-rich membrane microdomains – lipid rafts. Because of the previously observed tight functional connection of all three APP family member proteins (APP, APLP1 and APLP2), in this study we examined the effect of cholesterol accumulation on processing of APLP1 and APLP2 proteins. We used CHO NPC1-/- model cells and wild type cells as control cells (CHOwt). We showed that accumulation of cholesterol in CHO NPC1-/- vs. CHOwt cells leads to accumulation of β-secretase cleaved products - C-terminal fragments of APLP1 and APLP2 proteins (APLP1/2-CTF), similar to that observed for APP. In addition, we found that cholesterol reduction in CHO NPC1-/- cells caused reduced levels of APLP1/2-CTF fragments indicating that the effect of increased processing by β-secretase in NPC disease is directly linked to cholesterol levels. Given that the enzyme β-secretase has one of the key roles in generating Aβ peptides through the amyloidogenic pathway of APP protein degradation, these results contribute to the mechanism of cholesterol-effect in the pathogenesis of Alzheimer's disease.

Item Type: Thesis (Diploma thesis)
Keywords: amyloid precursor protein (APP), amyloid-β (Aβ), Alzheimer's disease, Niemann-Pick type C disease, cholesterol, APLP1/2 protein
Supervisor: Katušić Hećimović, Silva
Co-supervisor: Oršolić, Nada
Date: 2011
Subjects: NATURAL SCIENCES > Biology
Divisions: Faculty of Science > Department of Biology
Depositing User: Grozdana Sirotic
Date Deposited: 12 Jun 2014 08:36
Last Modified: 18 Sep 2014 09:24
URI: http://digre.pmf.unizg.hr/id/eprint/2360

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