Transgenic mouse assay for compounds affecting amyloid protein p

Details Transgenic mouse assay for compounds affecting amyloid protein p Transgenic mouse assay for compounds affecting amyloid protein p

1994-07-29

1998-02-24

Crouch, Deborah

Drug, bio-affecting and body treating compositions

In vivo diagnosis or in vivo testing

800 2, 800DIG1, 935 60, 935 62, A61K 4900, C12N 500, C12N 1500

Patent

active

057209367

ABSTRACT:
The construction of transgenic animal models for testing potential treatments for Alzheimer's disease are described. The models are characterized by a greater similarity to the conditions existing in naturally occurring Alzheimer's disease, based on expression of all three forms of the .beta.-amyloid precursor protein (APP), APP.sub.695, APP.sub.751, and APP.sub.770), as well as various point mutations based on naturally occurring mutations, such as the London and Indiana familial Alzheimer's disease (FAD) mutations at amino acid 717, and predicted mutations in the APP gene. The APP gene constructs are prepared using the naturally occurring promoter, as well as inducible promoters such as the mouse metallothionine promoter, which can be regulated by addition of heavy metals such as zinc to the animal's water or diet, and promoters such as the rat neuron specific enolase promoter, human .beta. actin gene promoter, human platelet derived growth factor B (PDGF-B) chain gene promoter, rat sodium channel gene promoter, mouse myelin basic protein gene promoter, human copper-zinc superoxide dismutase gene promoter, and mammalian POU-domain regulatory gene promoter. The constructs are introduced into animal embryos using standard techniques such as microinjection. Animal cells can be isolated from the transgenic animals or prepared using the same constructs with standard techniques such as lipofection or electroporation. The transgenic animals, or animal cells, are used to screen for compounds altering the pathological course of Alzheimer's Disease as measured by their effect on the amount and histopathology of APP and .beta.-amyloid peptide in the animals, as well as by behavioral alterations.

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