Project

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The molecular links between cholesterol homeostasis, membrane trafficking and Alzheimer's disease

English title The molecular links between cholesterol homeostasis, membrane trafficking and Alzheimer's disease
Applicant Rajendran Lawrence
Number 152496
Funding scheme SCOPES
Research institution Abteilung für Psychiatrische Forschung Universität Zürich
Institution of higher education University of Zurich - ZH
Main discipline Neurophysiology and Brain Research
Start/End 01.04.2014 - 31.03.2016
Approved amount 195'000.00
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All Disciplines (2)

Discipline
Neurophysiology and Brain Research
Cellular Biology, Cytology

Keywords (4)

Subcellular compartmentalization; Alzheimer`s Disease; Amyloid; BACE

Lay Summary (German)

Lead
Prof. Lawrence Rajendran from the University of Zurich will lead the Project with the Partners from Serbia and Croatia.
Lay summary

Die Alzheimer-Krankheit (AD) ist die häufigste neurodegenerativeErkrankung. Sie stellt eine ernsthafte Bedrohung für die Autonomie, Mobilitätund Gesamtfunktionalität des Patienten dar. Die Krankheit ist charakterisiertdurch die Plaquebildung aus Amyloidablagerungen und neurofibrullären Bündeln.

Wie diese Amyloidablagerungen entstehen, ist noch nicht bekannt. Bestimmte Gene und Umweltfaktoren werden jedoch mit der Entstehung der Krankheit in Zusammenhang gebracht. Die Ernährung spielt eine zusätzliche Rolle, insbesondere das Cholesterin. Es konnte gezeigt werden, dass mit hohen Cholesterinwerten die Menge der Amyloidablagerungen im Gehirn zugenommen hat. Ziel dieses Projekts ist es zu verstehen, wie sich das Cholesterin auf das Ausmass der Amyloidablagerungen auswirkt und abzuklären, inwiefern diese Erkenntnisse für eine AD-Therapie verwendet werden können.

Direct link to Lay Summary Last update: 11.06.2014

Responsible applicant and co-applicants

Publications

Publication
Emerging roles of extracellular vesicles in the nervous system.
Rajendran Lawrence (2014), Emerging roles of extracellular vesicles in the nervous system., in Journal of Neuroscience, 15482.
Function, therapeutic potential and cell biology of BACE proteases: current status and future prospects.
Vassar Robert (2014), Function, therapeutic potential and cell biology of BACE proteases: current status and future prospects., in Journal of Neurochemistry, 4, 4.

Awards

Title Year
Vontobel Prize 2016 2016
European Grand Prize 2015

Abstract

Aberrant proteolytic cleavage of the amyloid precursor protein (APP) leading to increased formation/accumulation of ß-amyloid peptide (Aß) is considered a central event in the pahogenesis of Alzheimer's disease (AD). Although much has been known about the Aß generation and its clearance, we still do not understand in great detail how Aß metabolism is altered in the most common late-onset form of AD (LOAD) and what are the molecular trigger(s) that initiate these events. In this project we will test the hypothesis that cholesterol metabolism and membrane trafficking are tightly linked and that their dysregulation leads to Alzheimer's disease. Abeta is generated within the amyloidogenic beta-secretase pathway through the cascade of cleavage events involving APP processing by proteases ß- (BACE1) and ?-secretases. All three proteins are transmembrane proteins, suggesting that lipid enviroment within the membrane and membrane trafficking could modulate their function and, thus, Aß formation. Indeed, ß-secretase cleavage of APP mainly occurs within the endocytic pathway, while retrieval of APP from endosomes to trans-Golgi-network via retromers seems protective by depleting APP from BACE1. Dysfunction of endosomes and retromers is an early pathological feature in AD, supporting that these two membrane trafficking routes play an important role in the pathogenesis of AD. In addition to Aß, ß-secretase APP processing pathway generates C-terminal APP fragments (CTFß) which have previously shown to mediate endosome dysfunction (Jiang et al., 2010) and are responsible for memory impairment and neurotoxicity characteristic for AD (Neve et al., 1996). Substantial amount of evidence has shown that altered neuronal membrane cholesterol level and/or subcellular distribution is implicated in aberrant APP processing and Aß/CTFß formation. However, the results are somewhat contradictory and we still do not have a complete understanding on how cholesterol can influence AD pathogenesis. In this project we will use a rare inherited cholesterol transport disorder Niemann-Pick type C (NPC), often referred as „childhood Alzheimer's“, to provide further evidence for the connection between APP metabolism, membrane misstrafficking and cholesterol homeostasis. Our approach is innovative as it utilizes an inherited single gene disorder to underpin the mechanism of the complex neurodegenerative diseases, such as AD. We will further examine the mechanistic details of an Alzheimer’s-like phenotype in NPC disease. In addition to Abeta peptide, which has been considered a central molecule in AD, in this project we will analyze how an increase in CTFß contributes to AD and NPC pathogenesis. We speculate that increased levels of CTFß, such as in AD and in NPC disease, regulate cholesterol homeostasis and modulate membrane trafficking within endocytic and/or retromer pathway, and, thus, contribute to the pathogenesis of AD and NPC disease. We will test the hypothesis that accumulation of APP-CTFß is, at least in part, responsible for membrane misstrafficking and altered cholesterol homeostasis in NPC disease. We will analyze whether Alzheimer's-like phenotype in NPC disease is due to retromer dysfunction, as observed in LOAD. In line with the recent finding that CTFbeta binds cholesterol (Barrett et al., 2012) and that APP can control cholesterol homeostasis and turnover (Pierrot et al., 2013), we will analyze the role of accumulation of CTFß on endosome/retromer pathway and cholesterol homeostasis, as well as the role of its G700XXXG704 cholesterol binding motif in this process. We believe that these studies will identify CTFß as a signal transduction molecule involved in regulating cholesterol homeostasis and/or membrane trafficking and will provide clues on molecular targets for development of novel therapies against this devastating disorder. This project involves collaboration between the three partners: Prof. L. Rajendran (University of Zurich, Switzerland), Dr. Mladenovic (Institute for Biological Research “Siniša Stankovic”, Beograd, Serbia) and Dr. Hecimovic (Rudjer Boskovic Institute, Zagreb, Croatia). Dr. Rajendran is an expert in the cell biology of Alzheimer's disease who will be responsible for the training of young scientists from Serbia and Croatia and for the transfer of the gained knowledge and technical skills to their home institutes. The partner from Croatia will serve as a bridge in translating their know-how to Serbian partner in order to help them to integrate more easily in the competitive research field on Alzheimer's disease. Through this project both partners from Serbia and Croatia will increase their scientific excellence, capacity, competitiveness and its international visibility. This will lead to their better integration in the European Research Area.
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