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Role of beta-secretase cleavage of non-amyloid substrates in Alzheimer`s Disease

English title Role of beta-secretase cleavage of non-amyloid substrates in Alzheimer`s Disease
Applicant Rajendran Lawrence
Number 130755
Funding scheme Project funding
Research institution Abteilung für Psychiatrische Forschung Universität Zürich
Institution of higher education University of Zurich - ZH
Main discipline Neurophysiology and Brain Research
Start/End 01.04.2010 - 31.03.2013
Approved amount 334'950.00
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All Disciplines (2)

Discipline
Neurophysiology and Brain Research
Cellular Biology, Cytology

Keywords (6)

Amyloid; BACE; Alzheimer`s Disease; Subcellualr compartmentalization; secretase, endosomes; Amyloid precursor protein

Lay Summary (English)

Lead
Lay summary
Alzheimer's disease (AD) is the most common form of neurodegenerative disease and prevalent in the aging population. This disease is characterized by the presence of amloid plaques in the brain accompanied by the formation of intraneuronal neurofibrillary tangles. The plaques are primarily composed of a peptide called the amyloid ? peptide which has been proposed to be the toxic molecule that causes Alzheimer's disease. The peptide is formed when two enzymes called ? and ?-secretases cleave a protein molecule called Amyloid precursor protein (APP). Hence both the enzymes are therapeutic targets, particularly ?-secretase as it is the first enzyme to cut APP in the A? producing reaction. This enzyme is also shown to be increased during aging and thus suggested to play a causative role in setting in of the disease. However, ?-secretase not only cleaves APP but also other proteins in the brain. Since cleavage of APP by ?-secretase would lead to the production of a peptide that would accumulate in amyloid plaques that could be seen in post-mortem brains, it cannot be concluded that cleavages of other proteins do not play a role in Alzheimer's disease. In this proposed project, we aim to address a provacative, alternate hypothesis for the cause of Alzheimer's disease. Could that be that proteins other than APP that could be cut by ?-secretase also play a role in Alzheimer's disease? If so, what roles do they play and how and where in the cell do they get cut by ?-secretase? These are the questions we would like to address in the framework of this proposal. On one hand it now enables us to understand if these other proteins have a role in AD and on the other, if they are not involved in AD but are important for the normal function of brain, we could now think about designing drugs that would only inhibit the cleavage of APP but not of other proteins. The outcomes of this project would help both in designing drugs as well for diagnosis.
Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
Superresolution Imaging of Amyloid Fibrils with Binding-Activated Probes
Ries Jonas (2013), Superresolution Imaging of Amyloid Fibrils with Binding-Activated Probes, in ACS Chemical Neuroscience, 22.
Active vaccination with the novel APP interacting protein ankyrin G reduces β amyloid pathology in APP transgenic mice
Santuccione Antonella (2012), Active vaccination with the novel APP interacting protein ankyrin G reduces β amyloid pathology in APP transgenic mice, in Molecular Psychiatry, 358.
BACE1 inhibition induces a specific cerebrospinal fluid β-amyloid pattern that identifies drug effects in the central nervous system.
Mattsson Niklas (2012), BACE1 inhibition induces a specific cerebrospinal fluid β-amyloid pattern that identifies drug effects in the central nervous system., in PLOS one, 31084.
Lipid-anchored drugs for delivery into subcellular compartments
Rajendran Lawrence (2012), Lipid-anchored drugs for delivery into subcellular compartments, in Trends in Pharmacological Sciences, 215.
Membrane trafficking pathways in Alzheimer's disease.
Rajendran Lawrence (2012), Membrane trafficking pathways in Alzheimer's disease., in Traffic, 759.
Retromers in Alzheimer's disease
Siegenthaler Barbara (2012), Retromers in Alzheimer's disease, in Neurodegenerative Diseases, 116.
Role of genes linked to sporadic Alzheimer’s disease risk in the production of β-amyloid peptides
Bali Jitin (2012), Role of genes linked to sporadic Alzheimer’s disease risk in the production of β-amyloid peptides, in Proceedings of the National Academy of Sciences USA, 15307.
Vesiclepedia: A Compendium for Extracellular Vesicles with Continuous Community Annotation
Kalra Hina (2012), Vesiclepedia: A Compendium for Extracellular Vesicles with Continuous Community Annotation, in PLOS Biology, 18.
Membrane anchored and lipid raft targeted β-secretase inhibitors for Alzheimer's disease therapy.
Ben Halima Saoussen (2011), Membrane anchored and lipid raft targeted β-secretase inhibitors for Alzheimer's disease therapy., in Journal of Alzheimer's Disease, 143.
Cellular basis of Alzheimer's disease
Bali Jitin (2010), Cellular basis of Alzheimer's disease, in Annals of Indian Neurology, 89.

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
Invited Talk, SOCRATES meeting Talk given at a conference 24.10.2013 Singapore, Singapore Rajendran Lawrence; Ben Halima Saoussen; Bali Jitin;
Invited Talk, 1st International BACE1 meeting Talk given at a conference 06.10.2013 Munich, Germany Rajendran Lawrence; Bali Jitin; Ben Halima Saoussen;
Plenary lecture, Omani Alzheimer’s Society Talk given at a conference 24.09.2013 Muscat, Oman Ben Halima Saoussen; Rajendran Lawrence; Bali Jitin;
Keynote Lecture, Molecular Medicine Congress Talk given at a conference 03.09.2013 Frankfurt, Germany Rajendran Lawrence; Bali Jitin; Ben Halima Saoussen;
Keynote lecture, Medical University of Vienna Scientists meeting Talk given at a conference 19.06.2013 Vienna, Austria Rajendran Lawrence; Bali Jitin; Ben Halima Saoussen;
Invited Talk, International Society of Extracellular Vesicles Talk given at a conference 17.04.2013 Boston, United States of America Bali Jitin; Rajendran Lawrence;
Invited Lecture, Neuropathology Individual talk 13.03.2013 Zurich, Switzerland Rajendran Lawrence; Bali Jitin;
Invited Talk, University of Bristol Individual talk 12.02.2013 Bristol, Great Britain and Northern Ireland Ben Halima Saoussen; Bali Jitin; Rajendran Lawrence;
Invited Lecture, Zing Conference on Neurodegeneration Talk given at a conference 01.12.2012 Xcaret, Mexico Ben Halima Saoussen; Rajendran Lawrence; Bali Jitin;
Invited Lecture, Department of Chemistry, ETH Zurich Individual talk 26.10.2012 Zurich, Switzerland Bali Jitin; Ben Halima Saoussen; Rajendran Lawrence;
Invited Lecture, Molecular Medicine Congress Talk given at a conference 16.10.2012 Madrid, Spain Bali Jitin; Ben Halima Saoussen; Rajendran Lawrence;
Invited Lecture, Sino Swiss Symposium Talk given at a conference 20.06.2012 Zurich, Switzerland Rajendran Lawrence; Bali Jitin; Ben Halima Saoussen;
Keynote Lecture, INCASAT meeting Talk given at a conference 25.05.2012 Panama City, Panama Bali Jitin; Rajendran Lawrence;
Award lecture, Eibsee meeting Talk given at a conference 28.10.2011 Munich, Germany Bali Jitin; Rajendran Lawrence;
Invited lecture, Regenerative medicine, University Hospital Zurich Individual talk 07.06.2011 Zurich, Switzerland Bali Jitin; Rajendran Lawrence;


Knowledge transfer events



Self-organised

Title Date Place
Raise.Rural (Research Awareness in Student Environment in Rural India) conference 04.01.2013 Thiruvannamalai, India
Raise.Rural 08.02.2012 Vandavasi, India
Raise.Rural 04.01.2012 Thiruvannamalai, India
Raise.Rural Conference 06.01.2011 Thiruvannamalai, India

Awards

Title Year
Distinction for PhD award for my first PhD Student, Mr. Jitin Bali. 2013
National Medal of Honor by the Govt. of Panama, President’s Prize, May 2011 2011
Hans und Ilse Breuer Research Prize, October 2010 With the 150,000 CHF, I bought the ECL machine for analysis of amyloids 2010
IBC’s Top 100 Scientists of the year 2009 2010

Associated projects

Number Title Start Funding scheme
146471 Role of beta-secretase cleavage of non-amyloid substrates in Alzheimer`s Disease 01.08.2013 Project funding

Abstract

1. SummaryBackground: Alzheimer’s disease (AD) is the most common form of neurodegenerative disease and prevalent in the aging population. A characteristic feature of the disease is the presence of amyloid-ß (Aß) containing plaques in the brain accompanied by the formation of intraneuronal neurofibrillary tangles (1). The predominant amyloid hypothesis postulates that Aß peptide, either in its soluble oligomeric conformation or in the amyloid plaque-associated form, is causally linked to neurodegeneration (2). Aß is liberated from a precursor molecule, termed amyloid precursor protein (APP), via proteolytic processing by ß- and ?-secretases (3). While Aß plaques appear to be a definitive marker for postmortem diagnosis of AD, its role in the pathogenesis still remains controversial and heavily debated. Mutations, either in the APP or the catalytic component of the ?-secretase, lead to enhanced deposition of Aß in plaques and consequently an early onset of the disease (4). However, the cause for late-onset AD is still unknown. Several candidate genes including APOE4 have been identified to be associated with the risk for AD. Anti-Aß therapies, either by inhibiting ß- ?-secretases or vaccination by Aß immunization procedures, are now being actively pursued for AD therapy (5).Working Hypothesis: ß-secretase (BACE1) is the rate-limiting enzyme in the production of Aß and hence the prime therapeutic target for AD (6). While no mutations in BACE1 gene have been observed to be associated with increased risk for AD, increased expression and activity have been reported to be associated with the disease (7). In support of these findings, BACE1 expression is tightly regulated at both the transcriptional and translational level (8, 9). However, it is now also known that APP is in fact a minor and low affinity substrate of BACE1 and that several other substrates do exist (10, 11). If BACE1 has essential functions through the cleavage of its physiological substrates, its therapeutic inhibition could result in adverse effects. Alternately, increase in BACE expression during Alzheimer’s disease could also lead to increased cleavages of other substrates and potentially play a role in the pathogenesis.Specific Aims: We would like to address three major questions as a part of this program: Specific Aim 1: In which subcellular organelle do the non-amyloid substrates get cleaved by BACE1? Specific Aim 2: What are the molecular and biochemical properties of BACE1 substrates?Specific Aim 3: If and how are these cleavages affected in Alzheimer’s disease?Experimental Design and Methods: To accomplish these aims, we intend to study the cell biology and biochemistry of BACE-1 cleavages of three newly identified substrates, namely: Neuregulin, PSGL-1, and the ß2 subunit of the voltage gated sodium channel. 1. Using our Anti-EctodomainNeo-EpitopeAntibody (AENEA) technology, we aim to produce antibodies that specifically recognize the ß-cleaved ectodomains of these substrates. This would serve as a valuable tool to probe the subcellular site of these cleavages and also aid in the histopathological analyses. 2. Cell biological examinations with genetic analysis of the substrates will be carried out in order to identify the subcellular site of ß-cleavage of these substrates and the sorting determinants in the proteins. Using reconstitution models, the affinities of these substrates for ß-secretase will be determined, which will allow us to construct a model as to how BACE1 cleavage of APP is regulated in the presence of other substrates. 3. The cell biological and biochemical studies will be complemented by histopathological analyses of the AD brain sections. Impact and Innovative Content: Results generated by these experiments will help to better understand the role of other substrates of BACE1 in Alzheimer’s disease. While most therapeutic measures are aimed at inhibiting Aß production by targeting BACE1, this study will also point out the pathophysiological consequences of inhibiting the cleavage of non-amyloid substrates. By studying the subcellular compartmentalization of the ß-cleavage of non-amyloid substrates, this study will further assist the design of specific BACE1 inhibitors, which inhibit APP cleavage without influencing the cleavage of other physiologically relevant substrates. If these cleavages are indicative of the pathological onset, then these would constitute novel biomarkers of the disease.
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