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Extracellular matrix and memory impairments in Alzheimer disease

Award Number: R01AG085359
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/01/2024
PERIOD OF PERFORMANCE END DATE: 03/31/2029

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Extracellular matrix and memory impairments in Alzheimer disease - PROJECT SUMMARY/ABSTRACT Alzheimer disease (AD) is the most common form of dementia worldwide[1]. AD is histopathologically defined by plaque- forming amyloid beta-protein (Aβ) and neurofibrillary tangles of phosphorylated tau protein. Amyloid and tau pathology typically begins in hippocampus and entorhinal cortex before spreading to anterior and lateral temporal structures of the brain, implicating them in hippocampal-dependent memory impairments. However, specific roles for either amyloid or tau in memory loss remain elusive. An important memory impaired in AD is social recognition memory, required to recognize familiar individuals. Social recognition memory engages a population of neurons in CA2 that are surrounded by specialized extracellular matrix structures called perineuronal nets (PNNs), which are believed to stabilize synapses. PNNs typically surround GABAergic inhibitory neurons, yet in the hippocampal CA2 region, PNNs encapsulate excitatory pyramidal neurons the very neurons implicated in social memory. PNNs are substrate for proteolytic enzymes such as MMPs know to be released with brain inflammation as occurs in AD. PNN disruption has indeed been reported in AD mouse models and postmortem AD human brains and we found PNNs in CA2 to be specifically degraded in human AD autopsies and mouse models of AD. We therefor hypothesize that amyloid and/or tau pathology triggers proteolysis of PNNs in hippocampus, destabilizing synapses in CA2 explaining impairments in social recognition memory. Using three established mouse models of AD that replicate either amyloid, tau or both pathologies we will (1) define a timeline for onset of PNN disruption, emergence of social memory deficits, and importance of underlying pathology, (2) examine whether PNNs play a causal role in social memory deficits in normal aging and in AD and (3) explore cellular mechanisms whereby PNNs contribute to this selective memory phenotype.


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: 2025 ( Subtotal = $686,552 )
2025	2025	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 EMMET ST N	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Aging Research	001	2	6/10/2025	NON-COMPETING CONTINUATION	$56,044
2025	2025	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 EMMET ST N	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Aging Research	000	2	3/21/2025	NON-COMPETING CONTINUATION	$630,508
														Subtotal = $686,552

Issue Date FY: 2024 ( Subtotal = $692,060 )
2024	2024	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 EMMET ST N	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Aging Research	000	1	5/27/2024	NEW	$692,060
														Subtotal = $692,060

Grand Total All Awards = $1,378,612

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Extracellular matrix and memory impairments in Alzheimer disease

Award Number: R01AG085359

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 06/01/2024

PERIOD OF PERFORMANCE END DATE: 03/31/2029

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