Beta-amyloid beta peptide (Abeta) is a 39-42 self aggregating peptide derived from the amyloid precursor protein (APP)l it is secreted by neurons and constitutes the principal fibrillar component of senile plaques. Extracellular Abeta is generally held to produce slowly developing toxic effects in brain and is linked to the development of dementia, but the mechanisms by which it does so remain obscure. Prior work by the applicants and others showed Abeta 1-42 is taken up primarily be cells in field CA1 in cultured hippocampal slices, sequestered into dense bodies corresponding to lysosomes, and results in lysosomal disturbances. Previous work has shown that pharmacologically induced lysosomal disturbance in cultured slices yields several signs found in the aging human brain and Alzheimer's disease (AD), including accumulation of APP C-terminal fragments and the formation of plaque- like structures, tau proteolysis, hyperphosphorylated tau, and the formation of tangle-like structures. These results suggests the proposed studies: we will test the hypothesis that uptake and sequestration of Abeta1-42 and consequent lysosomal dysfunction can, under appropriate conditions, generate characteristic features of aging and of AD (APP C- terminal fragments, Abeta accumulation, the development of tau hyperphosphorylation and tau proteolysis, and plaque- and tangle-like structures. A further hypothesis is that the aspartyl protease cathepsin D, which is elevated after lysosomal dysfunction, or a related protease is a critical link between Abeta sequestration and the development of certain AD-like pathology. The work will build upon preliminary data and will take advantage of the recent observation that antagonists of integrin receptors markedly increase Abeta sequestration in cultured slices, in contrast to their action in dissociated cells in which several Abeta1-42 and determine if it results in pronounced accumulation of APP C-terminal fragments and increased cathepsin D levels, both signs of lysosomal dysfunction.
Aims Three and Four will test the prediction that high levels of internalized Abeta lead to increased Abeta accumulation, the development of tau hyperphosphorylated and proteolysis, and early stage plaque- and tangle-like structures.
Aim Three will also test if plaque formation is more robust in slices from transgenic mice expressing human APP, both with and without integrin antagonist mediated enhanced uptake of Abeta.
Aim Five will test if inhibitors of cathepsin D block certain of the AD-related features induced by Abeta; knockout mice will be used to test if cathepsin D or a related protease is responsible. In sum, these studies will test specific and novel hypotheses about the links between amyloid and AD, improve a model system for studying AD- related pathology, and examine a new class of compounds with potential therapeutic value.
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