Alzheimer?s Disease (AD) is a prevalent neurodegenerative disease and the leading cause of age- related dementia. While the pathologic agent that causes AD remains controversial (A? vs. Tau) strong genetic, biochemical, anatomical and electrophysiological evidence have established that A? causes significant synapse loss and blocks induction of long-term potentiation (LTP), a form of plasticity critical for learning and memory. Soluble A? oligomers bind directly to excitatory synapses, but a significant fraction (~30- 40%) of synapses remain unbound. Correspondingly, a subset of synapses are spared from A?-triggered elimination, but the relationship between A? binding and elimination remains a fundamental question. Intriguingly, A?-mediated synapse loss requires activation of NMDA-type glutamate receptors (NMDARs), which gate Ca2+, a key second messenger for important forms of synaptic plasticity, including LTP. While pharmacologically blocking NMDARs prevents A?-induced synapse loss (suggesting that A? induces a gain of NMDAR function), A? also potently blocks LTP, suggesting that A? impairs NMDAR function, or downstream NMDAR signaling. Together, these results provide compelling evidence that NMDARs are a central mediator of A?-induced synaptotoxicity, yet there is a major gap in our understanding of how or whether A? influences NMDAR function. Furthermore, whether local synaptic activity plays a role in A? binding to synapses and whether only those synapses bound by A? are eventually eliminated remain fundamental questions. I will use a novel live cell imaging technique to assess changes in NMDAR function in response to A? at individual synaptic sites.

Public Health Relevance

Synaptic plasticity is thought to be the cellular correlate that underlies learning and memory and is disrupted in numerous disorders and diseases including Alzheimer?s Disease (AD). This proposal will investigate how the AD-associated protein, Beta Amyloid, affects proteins essential for synaptic plasticity and how these changes may result in the reduced number of neuronal connections seen in AD brains.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
5F31NS100403-02
Application #
9696538
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Corriveau, Roderick A
Project Start
2017-04-01
Project End
2020-03-31
Budget Start
2018-04-01
Budget End
2019-03-31
Support Year
2
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