Although it is generally agreed that accumulation of amyloid 13 (A,B) peptides in the brain contributes to the pathogenesis of Alzheimer's disease (AD), the cellular mechanisms that link A13 to AD dementia remain unresolved. Our studies showed that brief perfusion with A,B or its active fragment A,B2s 35 at subneurotoxic concentrations strongly inhibited the early and late phase of long-term potentiation (LTP) in the dentate gyrus of rat hippocampal slices, and impairment of late-phase LTP by A,13 could be rescued by calcineurin inhibitors. Furthermore, acute application of A132s 35 resulted in rapid but transient intracellular Ca2+ rises and enhanced Ca2+ oscillations in cultured hippocampal neurons. We have proposed here to further investigate the link between A, about induced alterations in Ca2+ signaling and inhibition of hippocampal LTP. It is hypothesized that A, about induced intracellular Ca2+ rises and subsequent activation of calcineurin, a Ca2+/calmodulin-dependent protein phosphatase, play the key role in LTP impairment. The Ca2+ transient may facilitate Ca2+-dependent inactivation or desensitization of NMDA receptor channels, suppressing induction of LTP. Activation of calcineurin may also shift the balance between a phosphatase cascade and several protein kinase systems, leading to changes in a LTP gating mechanism and/or alterations in the phosphorylation state of cAMP-response element binding protein (CREB). These signaling changes can in turn suppress the later components of LTP. Thus, via altered Ca2+ signaling A,13 interferes with both early and late components of LTP, which forms a possible cellular basis for memory deficits in Alzheimer's disease. Electrophysiological, immunocytochemical and neurochemical approaches will be used to test this hypothesis. The proposed Specific Aims are: 1) To further characterize the inhibitory action of A,B on both early and late components of dentate LTP; 2) To examine whether A,13 inhibits NMDA receptor channels of postsynaptic neurons to suppress LTP induction; 3) To determine whether A, about induced Ca2+ rises and calcineurin activation are responsible for inhibition of NMDA channels; 4) To deter aboutnine whether Ap activates the calcineurin/PP1 cascade to impair the inter aboutnediate phase of LTP; and 5) To determine whether A,13 alters CREB phosphorylation via a calcineurin-dependent mechanism, thus suppressing the late-phase LTP.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Project (R01)
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Special Emphasis Panel (ZRG1-BDCN-3 (01))
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Wagster, Molly V
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University of California Los Angeles
Schools of Medicine
Los Angeles
United States
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