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Nanoscale Mechanisms of Amyloid-Beta-Induced Disassembly of Excitatory Synapses

Award Number: F31AG099701
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 03/14/2027
PERIOD OF PERFORMANCE END DATE: 03/13/2028

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Nanoscale Mechanisms of Amyloid-Beta-Induced Disassembly of Excitatory Synapses - PROJECT SUMMARY Synapse loss correlates with cognitive decline in Alzheimer's Disease (AD), with Amyloid Beta (Aβ) toxicity playing a significant role. However, how Aβ affects synapses with different molecular makeup remains unclear. My research aims to address this gap by investigating these mechanisms at the single-synapse level using longitudinal stimulated emission depletion (STED) super-resolution microscopy. This approach is needed to identify how dynamic nano-scale processes that underlie synaptic function and plasticity are impacted by AD pathology. STED imaging has revealed that proteins within dendritic spines exhibit a highly ordered, modular nano-organization. PSD-95, a major and stable MAGUK protein at the postsynaptic density, follows this pattern, with the number of its nanoclusters scaling linearly with spine size. This modular organization has provided key insights into the structural plasticity of individual synapses. While Aβ causes a reduction in PSD-95 expression at synapses, my preliminary data indicate that Aβ disrupts PSD-95 organization in unexpected ways – with small spines with single PSD-95 being most vulnerable. Therefore, mechanisms that can rescue PSD-95 stability in vulnerable spines could be important for preventing synaptic dysfunction and loss in AD. Regulation of PSD-95 stability at spines is multifaceted, with activity-dependent and independent mechanisms playing a role. Blocking NMDAR activity rescues the destabilization of spines with a single PSD-95 nanomodule, indicating a role for NMDARs and Ca2+ signaling. My proposal will investigate which NMDAR subtypes regulate these processes to selectively disrupt PSD-95 in small spines. Evidence indicates that GluN2B-NMDAR may be involved. Another critical gap is determining how events at the spine surface translate into the destabilization of protein-protein interactions intracellularly. My preliminary data indicate that ephrin-B3 tans-synaptic organizing protein that directly interacts with PSD-95 may play a role by functioning as an intermediary between synaptic activity and PSD-95 stability via the Erk1/2-dependent phosphorylation of S332 residue of ephrin-B3. In my preliminary data, Aβ increased S332 phosphorylation of ephrin-B3 in an Erk1/2 and NMDAR-dependent manner. I hypothesize that Aβ binding to the spine surface will disrupt key protein-protein interactions that will increase PSD-95 mobility in small spines with single nanomodule. Aim 1 will explore the role of NMDAR subtypes in Aβ-dependent destabilization of small spines. Aim 2 will investigate the role of ephrin-B3/PSD-95 interaction in regulating Aβ- induced synaptotoxicity. I will use both fixed and live-cell STED imaging in combination with quantal Ca2+ analysis of single spines to determine signaling mechanisms utilized by Aβ to disrupt dynamic processes that are key for synaptic maintenance, function, and plasticity. This project will provide mechanistic insights into key events in early AD that may lead to novel therapeutic targets. Backed by WVU Neuroscience, my sponsor and co-sponsor, this work will prepare me for a successful career as an independent investigator in neuroscience.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $50,114 )
2026	2026	WEST VIRGINIA UNIVERSITY RESEARCH CORPORATION	886 CHESTNUT RIDGE ROAD	MORGANTOWN	WV	26505	MONONGALIA	USA	Aging Research	000	1	9/14/2026	NEW	$50,114
														Subtotal = $50,114

Grand Total All Awards = $50,114

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Nanoscale Mechanisms of Amyloid-Beta-Induced Disassembly of Excitatory Synapses

Award Number: F31AG099701

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 03/14/2027

PERIOD OF PERFORMANCE END DATE: 03/13/2028

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