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Cellular and animal models of Alzheimer's disease molecular pathology

Objective

Objectives:
To develop cell culture and transgenic model for Alzheimer's disease (AD) synaptic loss, neurodegeneration and pathophysiology, to study the mechanism, to analyze the functional consequences, to evaluate strategies and model compounds aimed to prevent and cure and treat AD neurodegeneration and thus to provide industries assay systems for the development of new drugs relevant for the treatment of AD.

Brief description:
The pathophysiology of AD involves severe synaptic dysfunction, neuronal degeneration and cell death. Our rationale is, understanding the role of neuronal degeneration and death in AD disease progression depends on elucidation of the underlying regulatory mechanisms. This makes the availability of cell culture and animal models an absolute necessity that allow an indepth study of these molecular mechanisms. Our cellular and transgenic approach offers unique advantages by combining the unsurpassed advantages of in vitro systems with the complementing living model.
The present programme is geared towards a better understanding of the pathophysiological process which is key to the discovery of new treatment principles. The programme goal is to establish both in vitro (cellular) and in vivo models of the pathopysiology of AD and thus to provide assay systems for the discovery of new drugs relevant for the treatment of AD. The specific aims are to generate cell culture models to elucidate the molecular mechanism of AD chronicity which depends on the deposition of Aß amyloid by coexpression of the Alzheimer amyloid precursor protein (APP) and clinical mutants therof with the other AD genes presenilin 1 (PSI), presenilin 2 (PS2) and different alleles of the ApoE gene, exposing these cells to Aß amyloid, to establish relation of Aß deposition to cell dysfunction and cell death, and to test curative and preventive principles, including drugs and gene regulation. Generate multiple-gene transgenic mouse strains expressing amyloidogenic fragments of the APP gene and human wild-type and mutated APP genes, presenilin genes PSl and PS2, and to combine the four genetic factors involved in AD etiology by crossing the former transgeneic mice with apoE gene-disrupted mice. Analysis of transgenic animals to their central nervous system regeneration and synaptic plasticity by studying cholinergic and non-cholinergic ascending modulatory systems, intrinsic peptide positive GABA neurons, synaptic density, neuronal sprouting capacity following selected brain lesions. To elucidate the mechamism of apoptosis in AD by studying the relationsship between apoptosis and the AD hallmark molecule APP and its breakdown product Aß amyloid peptide. Analyse the specificity of neuronal susceptibility to damage in AD by examining the specific expression of apoptotic machinery in distinct brain areas in AD. Examine the occurence of apoptotic cell death in the transgenic animals both in vitro primary neuronal cultures and in vivo. Assess the activiation/inhibition of the intracellular kinases, a key step in triggering of the apoptotic process. Examine the hypothesis that the distinct effects of the apoE isoforms on cellular functions are mediated by effects on the neuronal cytoskeleton. Analyze the effects of distinct apoE isoforms on neuronal susceptibility of oxidative stress and on neuronal repair mechanisms.

Keywords:
Alzheimer's disease, brain aging, synaptic loss, neuronal dysfunction, neurodegeneration, disease genes, function of Aß amyloid, neuronal transport of APP, transgenic models, apoE function, apoptosis.

Funding Scheme

CSC - Cost-sharing contracts

Coordinator

RUPRECHT-KARLS-UNIVERSITAET HEIDELBERG
Address
Im Neuenheimer Feld 282
69120 Heidelberg
Germany

Participants (3)

Rhône Poulenc Rorer Recherche et Développement
France
Address
13,Quai Jules Guesde
94403 Vitry-sur-siene
Tel Aviv University
Israel
Address
Ramat Aviv
69978 Tel Aviv
UNIVERSITY OF KUOPIO
Finland
Address
9,Savilahdentie 9 G, 2Nd Floor
70210 Kuopio