Although our understanding of the pathogenesis of Alzheimer's disease (AD) has advanced enormously over the past decade, the link between the pathology of the disease and its devastating cognitive symptoms remains unclear. An exciting possibility for this connection recently came to light in the discovery of a direct interaction between the At3 peptide found in amyloid lesions of AD and a neurotransmitter receptor that modulates synaptic function in parts of the brain most afflicted by the disease. Not only does the o_7 acetylcholine receptor bind strongly and specifically to A_, but in so doing, its response to stimulation by acetylcholine is significantly altered. This interaction could substantially affect cholinergic transmission in areas of the brain rich in both A[3 and ix7, including the cortex and the hippocampus. However, most of the research to characterize this interaction to date has focused the peptide's acute effects in preparations often quite unrelated to the adult brain. Our proposed experiments will extend these earlier findings in several important ways. First, we will address the functional consequences of A[5 exposure by examining ct7-mediated neurotransmitter release and calcium homeostasis in hippocampal neurons. Second, we will use an acute slice preparation from postnatal animals that retains much of the normal neuronal connectivity found in vivo. Third, we will explore how prolonged exposure to A[3 influences et7-mediated synaptic function, and how this compares to the peptide's acute effects. Fourth, we will examine whether binding to a7 later promotes aggregation of A[5 and the formation of amyloid plaques. Finally, we will determine the binding site for A[3 on the ct7 receptor. Thus our proposed research will assess the functional and pathological changes caused by the binding of Ai5 to ct7, and determine the site on the receptor where this interaction takes place with the long- term prospect of pharmaceutical intervention.
