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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21AG058005-01
Application #
9434266
Study Section
Cellular and Molecular Biology of Neurodegeneration Study Section (CMND)
Program Officer
Wise, Bradley C
Project Start
2017-01-01
Project End
2019-12-31
Budget Start
2017-01-01
Budget End
2018-12-31
Support Year
1
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Colorado Denver
Department
Pharmacology
Type
Schools of Medicine
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045