Sunday, May 18, 2025
5/18/2025
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.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).