Transgenic mouse and rat models for alzheimer's disease

Informazioni relative al progetto

ID dell’accordo di sovvenzione: BIO4960743

Progetto chiuso

Data di avvio 1 Novembre 1996

Data di completamento 31 Ottobre 1999

Finanziato da

• Specific research, technological development and demonstration programme in the field of biotechnology, 1994-1998

Costo totale

Nessun dato

Contributo UE

Nessun dato

Coordinato da

FLANDERS INTERUNIVERSITY INSTITUTE FOR BIOTECHNOLOGY VZW
Belgium

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Risultati sfruttabili

Transgenic mouse and rat models for Alzheimer's Disease

Transgenic mouse strains have been generated whose brains produce large amounts of human APP, human PS-1 or both. First over expression of APP, resulted in a robust phenotype recapitulating behavioral and pathological symptoms and of AD patients: increased aggression, anxiety, neophobia, posture freezing, decreased thigmotaxis, increased tendency for occasional seizures, with a progressive increase with age. In the APP-transgenic mice, a relation is sought with differentially altered responses to glutainmatergic agonists, i.e. increased sensitivity to kainic acid, refractory response to NMDA. As second important feature, the APP-transgenic mice suffered a severe cognitive defect as measured in the standard Morris watermaze, importantly, the deficit was observed in animals of only 4 months old. Longitudinal analysis, i.e. progression of the cognitive defect, will be correlated to brain biochemistry and physiology by multi-disciplinary analysis: qualitative and quantitative immuno-histochemistry for neuronal and synaptic markers, biochemical intermediates of APP, i.e. the amyloid peptides 40 and 42, the C terminal "stubs". Third important feature is the development of amyloid plaques in the brain of APP/London transgenic mice when older than 12 months. The biochemical, histological and immunohistochemical appearance and reactivity of the plaques are indistinguishable of those observed post-mortem by pathological analysis of brain of AD patients. The transgenic APP mice recapitulate sallent features of AD patients: early behavioral, "psychiatric" and cognitive defects, including decreased LTP (long term potentation) and late amyloid pathology. Further characterization is aimed at the most early stages of the disease to develop new therapeutic targets and detect new diagnostic features. The APP-transgenic mice are being validated as pre-clinical models for third-level screening of novel drugs and pharmaceutical compound libraries.