Proteolysis of apoE and Alzheimer's pathology

点击翻译按钮获取中文摘要

DESCRIPTION (provided by applicant): Although abundant new information has recently been collected on the genetic and environmental risk factors associated with Alzheimer's disease, there is still no consensus on the critical pathway leading to neuropathology. The "amyloid hypothesis", which dominates much current research effort, has both strengths and weaknesses. One aspect of the postulated role for amyloid that is particularly contentious is the extent to which it is a direct cause of neuronal degeneration, as opposed to participating in a cascade of events that ultimately leads to neuronal dysfunction and death. Other genetic risk factors for proteins involved in AD include apolipoprotein E (apoE) and there is accumulating evidence that apoE4 may directly contribute to AD neuropathology. In particular, apoE4 has been shown to exhibit neurotoxic effects in vitro. This toxicity may be associated with proteolytic generation of a shortened form of apoE (truncated apoE), which is more abundant in AD brain tissue. In addition, several lines of evidence suggest that a C-terminal fragment of apoE binds to, and co-localizes with, amyloid. The work proposed here will examine the hypothesis that proteolytic fragments of apoE contribute to both neuropathology and amyloid deposition. A combination of immunohistochemical, biochemical, and tissue culture studies will be used to: examine the extent of apoE proteolysis in human brain and apoE transgenic mouse brain; identify the cellular source of apoE and its proteolysis in the CNS; study the role of specific receptors in apoE neurotoxicity; study the effect of C-terminal apoE on ABeta aggregation and activity; and localize apoE fragments at sites of AD pathology. The goal is to pursue evidence in support or against the major hypothesis that proteolysis of apoE contributes to AD pathology.