increasing evidence from this and other laboratories has implicated compromised transcription, translation, and/or RNA metabolism in the Alzheimer's Disease (AD) brain. Therefore, the proposed investigations are designed to explore these cellular functions and their relationship to pathological markers (amyloid deposits and, where appropriate, neurofibrillary tangles) in AD brain tissue and in model systems. These studies appear feasible since this laboratory previously showed that the postmortem brain contains sufficiently intact polysomes and mRNA for postmortem protein synthesis to occur. More recently we demonstrated incorporation of 3H uridine by Ad brain tissue in vitro which indicates the preservation of transcriptional machinery in conventionally obtained postmortem brains. In related experiments we shall assess whether or not the transfected cells and transgenic mice (from Project 1) that overexpress the amyloid gene are useful adjuncts to the study of the Ad brain. Using cells and mice we shall address the question of whether or not overproduction of amyloid is associated with altered transcription and or translational processes. Furthermore, we propose to examine the response of the transfected cells to specific trophic factors in order to evaluate the consequences of amyloid overproduction on the differentiation process. The latter studies have implications for neuronal plasticity. The proposed experiments are designed to serve as the functional counterpart to the neuroanatomic investigations that are presented in Project 2. In both projects, the same antibodies to discrete cellular markers will be used (antibodies to polymerases, ribosomal proteins, ribonuclease inhibitor protein, neurofilament protein, GFAp, paired helical filaments, A4 amyloid) and the data from Projects 1 and 2 will be analyzed concurrently.
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