The overall hypothesis is that the cellular responses to amyloid beta (A beta ) that culminate in the cell dysfunction and degeneration characteristic of Alzheimer disease (AD) are dependent on the specific structure of the supramolecular aggregates formed by the A beta peptides. The applicants propose that part of the process of maturation of the predominantly diffuse, non-neuritic amyloid plaques of """"""""normal"""""""" aging into the neuritic plaques associated with dementia involves the generation of these specific A beta structures. Extending this hypothesis, the applicants further propose that the generation of """"""""toxic"""""""" supramolecular structures of A beta aggregates can be influenced by the presence of other plaque components, particularly those components derived from glia, and that responses of glial cells contribute to an environment that facilitates and enhances the formation of these bioactive A beta forms. It is their contention that glia are not just passive bystanders, but are a part of the pathogenesis process. They postulate that A beta toxicity can be mediated through its effects on glia, that glia-derived proteins can influence the structure of A beta and its effects on neurons, and that these processes are relevant to the actual neuropathology seen in the AD brain. The questions being addressed in these studies are: What does A beta do to glia? What do glia do to A beta structure and activity? Are glia relevant to AD neuropathology? Three aims are proposed to address these questions. 1) They will evaluate the effects of A beta on glia. Specific A beta aggregates will be prepared, characterized by atomic force microscopy (AFM), and tested for activity on cultures of rat primary astrocytes. The investigators will examine the effects of A beta on the levels and activity of six relevant glial proteins: a 1-antichymotrypsin (ACT), apolipoprotein E (apoE), apoJ, butyrylcholinesterase (BChE), interleukin-1 (IL-1), and S100 beta . 2) They will evaluate the effects of glia on A beta structure and neurotoxicity. In co-aggregation experiments, they will evaluate AFM structure of A beta aggregates formed in the presence of the six glial proteins studied in aim 1. The investigators will also test A beta -evoked neurotoxicity in the presence of these six glial proteins and in glial-neuronal co-cultures. 3) They will correlate the presence and distribution of glial proteins with plaque type in AD brain. They will determine the regional distribution and immunoreactive density of the six glial proteins in AD and control brain tissue, and establish correlations with the distribution of non-neuritic vs neuritic plaques. This system examination should provide insight into how A beta affects glia, and how glia participate in amyloid plaque progression and development of neurotoxicity.
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