AD is a devastating neurodegenerative disorder characterized by progressive loss of memory and cognitive functions. The long-term goal of this research is to elucidate the role of beta-amyloid protein (Ab) and apolipoprotein (apo)E in the pathogenesis of Alzheimer's disease (AD). A possible role for Ab as either a marker for AD onset and progression or as a causative factor is supported by its marked accumulation in neuritic plaques and cerebrovascular sites. Genetic, epidemiological, and biochemical evidence is mounting that apoE exerts an isoform specific-effect on the rate or extent of development of AD. The investigators already demonstrated that overexpression of a C-terminal region of amyloid precursor protein (APP) leads to the production of Ab-bearing 14 and 15 kDa neurotoxic fragments in cultured neuronal cells. In addition, the investigators have already created transgenic mice that overproduce these 14 and 15 Kda fragments. These mice are said to produce more protein product in brain than reported by other investigators. Although they have not observed any obvious pathological changes in the brains of their transgenic mice (up to 26 months), amyloid deposits have been observed in the intestines of these mice. They hypothesize that other factors may be necessary for the induction of neuropathological changes associated with AD, such as expression of specific apoE alleles, or quantities of these alleles. Thus, the Specific Aims of this research proposal are to: (1) establish transgenic mice overexpressing human apoE3 and apoE4; (2) establish transgenic mice overexpressing Ab with different apoE genotypes; and (3) analyze transgenic mouse lines for AD symptoms. ApoE allele specific CDNA constructs will be made with a cytomegalovirus promoter system. Overexpression of human apoE (apoE3-e3 mice and apoE4-e4 mice) will be established in mice lacking endogenous apoE expression (apoE """"""""knock-out"""""""" mice) by a combination of transgenic and breeding schemes. These mice will be studied and crossed to mice overexpressing Ab to determine the effects of each genetic change and gene interactions on the propensity of AD pathology. The development of animal models expressing various forms of apoE in the presence of marked amyloid expression may provide excellent tools in which to study the progression, prevention, and treatment of AD.
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