Alzheimer disease (AD) is marked by a progressive degenerative neuropathology in the cerebral cortex and hippocampus. The primary morphological signs of the disease are the presence of intracellular neurofibrillary tangles as well as neuritic plaques and cerebrovascular amyloidosis. The neuritic plaque is a complex structure composed of a central amyloid core surrounded by a cluster of dystrophic neurites and glia. The major component of the neurite plaque is a 4.2 kDa peptide termed the amyloid beta-protein (AbetaP) or A4 peptide. AbetaP exists as a component of at least three distinct precursor proteins, referred to as APP695, APP751, APP770. The pathological process leading to the production of the amyloid protein is not known, although it seems that aberrant degradation of APP is involved. Research in our laboratory has shown that the full length Amyloid precursor (APP) protein is associated with the cytoskeletal component of the cell in both glial and neuronal cell cultures and in brain tissue. This association is modulated by at least two factors, e.g. cell density and protein kinase C, and it requires intact microtubules. In addition, the human and rat brains contain truncated APP forms associated with the cytoskeleton, which derive from the C-terminal portion of the APP protein and encompass all of the AbetaP sequence. The presence of these forms in brain tissue suggests that in addition to the non-amyloidogenic cleavage pathway which produces the secreted APP forms, other potentially amyloidogenic cleavage pathways exist which produce APP fragments containing the intact AbetaP sequence. These observations have implications for both the physiological function of APP and the production of the AbetaP from its precursor. Here we propose to further characterize the factors mediating the cytoskeletal association of all APP forms, and to examine any differences in the cytoskeletal association of APP between normal and AD brain.
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