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Memory loss in Alzheimer disease: underlying mechanisms and therapeutic targets

Objective

MEMOSAD aims at defining the molecular mechanisms of Abeta- and Tau-induced synaptotoxicity and at developing disease-modifying therapeutics for the prevention of memory loss in Alzheimer disease (AD). Insoluble aggregates of the two proteins provide the pathological hallmarks of this incurable brain disorder. Early stage AD is characterized by a remarkably pure impairment of declarative memory and several lines of evidence suggest that this memory impairment is independent of the insoluble aggregates, does not require neuronal death and is caused by subtle and transient synaptic changes. The toxic Abeta and Tau species that cause synaptic dysfunction, their mechanism of toxicity and the link between both pathologies remain largely unknown, but recent data suggest that Abeta accumulation triggers Tau pathology. Consequently, primary neuronal cultures and animal models (C.elegans,zebrafish,mouse) will be employed to define the pathologic pathways leading from Abeta through Tau to synaptotoxicity. Initial experiments will investigate the effect of well-defined Abeta species on long term potentiation, synaptic morphology, gene expression, Tau phosphorylation/aggregation, axonal transport and behaviour. Similarly, we will investigate the functional consequences of Tau misfunction, aggregation, hyperphosphorylation and missorting in various cell culture systems (retinal ganglion cells, primary hippocampal neurons, organotypical slices) and animal models, especially with regard to intraneuronal trafficking and synaptic function. Once the toxic Abeta and Tau species are known and their mechanism of toxicity are defined, we will investigate how these pathways interact. Unravelling the pathologic pathways that lead from Abeta through Tau to synaptotoxicity and memory loss should reveal novel points for therapeutic intervention. Our aim is to deliver 3 or 4 validated therapeutic targets and at least 2 compounds with demonstrated therapeutic efficacy in mouse models of AD.

Field of science

  • /medical and health sciences/basic medicine/pathology
  • /medical and health sciences/basic medicine/neurology/alzheimer

Call for proposal

FP7-HEALTH-2007-A
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Funding Scheme

CP-FP - Small or medium-scale focused research project

Coordinator

VERUM- STIFTUNG FUER VERHALTEN UND UMWELT
Address
Theresienstrasse 6-8
80333 Muenchen
Germany
Activity type
Other
EU contribution
€ 333 496
Administrative Contact
Franz Adlkofer (Prof.)

Participants (9)

VIB VZW
Belgium
EU contribution
€ 420 000
Address
Rijvisschestraat 120
9052 Zwijnaarde - Gent
Activity type
Research Organisations
Administrative Contact
Wim Goemaere (Mr.)
Klinik Max Planck Institut für Psychiatrie
Germany
EU contribution
€ 420 000
Address
Hofgartenstrasse 8
80539 Muenchen
Activity type
Private for-profit entities (excluding Higher or Secondary Education Establishments)
Administrative Contact
Elke Spader (Ms.)
UNIVERSITE DE LILLE II - DROIT ET SANTE
France
EU contribution
€ 420 000
Address
Rue Paul Duez 42
59800 Lille
Activity type
Higher or Secondary Education Establishments
Administrative Contact
Marie Gompel (Dr.)
UNIVERSITY COLLEGE DUBLIN, NATIONAL UNIVERSITY OF IRELAND, DUBLIN
Ireland
EU contribution
€ 419 804
Address
Belfield
4 Dublin
Activity type
Higher or Secondary Education Establishments
Administrative Contact
Donal Doolan (Mr.)
LUDWIG-MAXIMILIANS-UNIVERSITAET MUENCHEN
Germany
EU contribution
€ 239 996
Address
Geschwister Scholl Platz 1
80539 Muenchen
Activity type
Higher or Secondary Education Establishments
Administrative Contact
Mathias Becker (Mr.)
ALBERT-LUDWIGS-UNIVERSITAET FREIBURG
Germany
EU contribution
€ 240 000
Address
Fahnenbergplatz
79098 Freiburg
Activity type
Higher or Secondary Education Establishments
Administrative Contact
Gabriela Hafke-Wessel (Ms.)
UNIVERSIDAD AUTONOMA DE BARCELONA
Spain
EU contribution
€ 240 000
Address
Calle Campus Universitario Sn Cerdanyola V
08290 Cerdanyola Del Valles
Activity type
Higher or Secondary Education Establishments
Administrative Contact
Katja Schustakowitz (Ms.)
KATHOLIEKE UNIVERSITEIT LEUVEN
Belgium
EU contribution
€ 200 400
Address
Oude Markt 13
3000 Leuven
Activity type
Higher or Secondary Education Establishments
Administrative Contact
Marion Wolpers (Ms.)
SENEXIS LTD
United Kingdom
EU contribution
€ 65 000
Address
Babraham Research Campus
CB22 3AT Cambridge
Activity type
Private for-profit entities (excluding Higher or Secondary Education Establishments)
Administrative Contact
Mark Treherne (Dr.)