Widely recognized as one of the primary pathological agents responsible for Alzheimer's disease (AD), ?-amyloid peptide triggers a broad host of cellular pathologies including synapse loss, tau phosphorylation, and ultimately cell death. One of the earliest manifestations of AD in the central nervous system is the loss of excitatory synapses and impaired function at remaining synapses, which precedes widespread neuronal cell death. Accumulating evidence suggests that synapse elimination and dysfunction is triggered by soluble oligomeric assemblies of the beta-amyloid peptide (A?o). Intriguingly, A?o-mediated synapse loss requires activation of NMDA-type glutamate receptors (NMDARs), which conduct Ca2+, a critical second messenger for diverse forms of synaptic plasticity required for normal cognitive function. How or whether A?o directly influences synaptic NMDAR function is unclear. We recently found that Ca2+ entry through synaptic NMDARs was potently impaired following exposure to concentrations of A?o similar to those found in the cerebrospinal fluid of healthy individuals. Here we propose to dissect the mechanisms and signaling pathways responsible for A?o-induced NMDA receptor impairment and explore the possibility that A?o could play a normal role in NMDA receptor regulation in the healthy brain. If true, this would be a completely new and important function for amyloid peptides and would yield new insights into how these proteins contribute to synaptic dysfunction when misregulated.
Alzheimer's Disease (AD) is a prevalent neurodegenerative disease and the leading cause of age- related dementia. There is strong evidence that beta-amyloid (A?) is one of the principal neurotoxic agents responsible for AD. The goal of this work is to understand how A? triggers loss of excitatory synaptic connections in the central nervous system. !
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