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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 146471
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 01.08.2013 - 31.10.2016
Approved amount 304'950.00
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All Disciplines (2)

Discipline
Neurophysiology and Brain Research
Cellular Biology, Cytology

Keywords (4)

Amyloid; Alzheimer`s Disease; Subcellular compartmentalization; BACE

Lay Summary (German)

Lead
Entwicklung ß-secretase Inhibitoren für die Therapie der Alzheimer Krankheit
Lay summary
Die Alzheimer Demenz (AD) ist die häufigste neurodegenerative Erkrankung weltweit und ein häufiges Leiden unter älteren Menschen. Charakteristisches histopathologisches Merkmal im Gehirn der Betroffenen ist das Auftreten von extrazellulären b-Amyloid (Ab) Plaques zusammen mit intrazellulären neurofibrillären Aggregaten aus Tau-Protein. Der heutige Stand der Forschung weist dem Ab-Peptid eine zentrale Rolle bei der Entstehung von AD zu. Ab-reduzierende Massnahmen stehen daher im Fokus bei der Suche nach therapeutischen Strategien im Kampf gegen die Krankheit. Aβ wird durch sequenzielle Proteolyse des Amyloid-Vorläufer-Proteins (APP) durch β- und γ-Sekretase generiert. Eine Reduzierung der Menge an Ab im Gehirn kann entweder durch eine verminderte Produktion von Ab erreicht werden (durch Hemmung von b- oder g-Sekretase) oder aber durch eine Stimulation des Abbaus von Ab (mittels Immuntherapie). g-Sekretase Hemmstoffe sind von wachsendem Interesse in der derzeitigen Forschung. In früheren klinischen Studien erreichten sie bereits Phase III. Die Tests mussten dann jedoch eingestellt werden, da toxische Nebenwirkungen auftraten. Diese waren vermutlich das Resultat einer gehemmten Prozessierung anderer wichtiger g-secretase Substrate, z.B. Notch. Da auch b-Sekretase (BACE1) viele physiologisch wichtige Substrate hat, z.B. Neuregulin 1 (NRG1), stellt auch die generelle Hemmung dieser Sekretase keine sichere Alternative da. Für eine sichere Therpaie  werden daher g-Sekretase Modulatoren benötigt, welche die Prozessierung von Nicht-Amyloid Substraten nicht beeinträchtigen. Für die Entwicklung solcher Modulatoren bedarf es zunächst einer detaillierten molekularen, biochemischen und zellbiologischen Untersuchung der verschiedenen  BACE1-Substrate.

Direct link to Lay Summary Last update: 09.08.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
Specific Inhibition of b-Secretase Processing of the Alzheimer Disease Amyloid Precursor Protein
Saoussen Ben Halima123 Sabyashachi Mishra412 K. Muruga Poopathi Raja5 Michael Willem6 Antonio (2016), Specific Inhibition of b-Secretase Processing of the Alzheimer Disease Amyloid Precursor Protein, in Cell Reports, 14, 1-15.

Collaboration

Group / person Country
Types of collaboration
Christian Haass Germany (Europe)
- Publication
- Research Infrastructure
- Exchange of personnel
Division of Psychiatry Research, University of Zurich Switzerland (Europe)
- Exchange of personnel
Proterus Germany (Europe)
- Publication
- Exchange of personnel

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
BACE in health and disease Talk given at a conference Selective inhibition of BACE processing of APP 08.09.2016 Munich, Germany Rajendran Lawrence; Ben Halima Saoussen;
National Institute of Health Individual talk Insulin and Nutrient sensing pathway is involved in amyloid formation 27.11.2015 Bethesda, United States of America Rajendran Lawrence;
FEBS meeting Talk given at a conference Insulin and nutrient signaling promotes amyloid formation 15.06.2015 Berlin, Germany Rajendran Lawrence;
AD/PD meeting Talk given at a conference Cellular complexity in Alzheimer's disease 28.03.2015 Nice, France Rajendran Lawrence;


Knowledge transfer events



Self-organised

Title Date Place
Raise Rural - Science symposium for students from rural parts of india 03.01.2015 Thiruvannamalai, India

Communication with the public

Communication Title Media Place Year
Media relations: radio, television Der Nebel des Vergessens – Leben mit Demenz NZZ German-speaking Switzerland 2017
Media relations: print media, online media http://speciality.medicaldialogues.in/new-drug-candidate-for-alzheimers-shows-promise/ International 2016
Media relations: radio, television http://www.srf.ch/sendungen/puls/forschung/neuer-wirkstoff-blockiert-alzheimer-enzym SRF German-speaking Switzerland 2016
Media relations: print media, online media New drug candidate for Alzheimer's shows promise Business Standard International 2016
Media relations: print media, online media Researchers work to block harmful behavior of key Alzheimer's enzyme Science Daily International 2016
Media relations: print media, online media Safe, effective drugs for Alzheimer's in the offing Times of India International 2016

Awards

Title Year
European Young Investigator Grand Prize 2016
Vontobel Prize 2016

Use-inspired outputs


Start-ups

Name Year

Associated projects

Number Title Start Funding scheme
130755 Role of beta-secretase cleavage of non-amyloid substrates in Alzheimer`s Disease 01.04.2010 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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