Animal models are critical for studies of the etiology and potential pharmacological interventions of Alzheimer's disease (AD) and other amyloidoses, including cerebral amyloid angiopathy (CAA). The histopathology of AD and CAA includes brain parenchymal and vessel wall deposits of amyloid beta-protein (Abeta), a degradation production of beta-amyloid precursor protein (betaAPP). Mutations in the betaAPP gene exist in a few families with early onset familial AD (FAD) or CAA. The mutations segregate with the diseases, implying a role in amyloidogenesis. However, the amyloid fibrils are usually processing products of a normal precursor protein suggesting that amyloid associated proteins, such as apolipoprotein E and J, may play a crucial role in amyloid formation. The goals of this project are to establish transgenic models of AD and CAA, to determine from which tissues the amyloid rises, and to study the role of apolipoproteins E and J in amyloidogenesis in transgenic animals.
The specific aims of this proposal are: 1) to develop an animal model of CAA using vascular smooth muscle, neuronal and/or liver-specific promoters directing over-expression of wild type or amyloid/Dutch mutation (HCHWA-D); 2) to reduce established and develop new models of parenchymal amyloidosis, including a study of the microanatomy of amyloid deposition using a regionally-restricted neuronal promoter; and 3) to construct transgenic animal over-expressing apolipoprotein J in astrocytes in order to study the role of this protein in solubilization of amyloid peptides. Transgene expression will be assessed using Western, ELISA immunocytochemical and in situ assays. Histopathology examinations will be performed on all animals with appropriate levels of transgene expression. Crosses of animals with amyloid deposition, vascular and/or parenchymal, will be made with animals with engineered apoJ and apoE phenotypes to assess the effects of these amyloid associated proteins on amount and rate of amyloid deposition.
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