# Extracellular matrix and memory impairments in Alzheimer disease

> **NIH NIH R01** · UNIVERSITY OF VIRGINIA · 2024 · $692,060

## Abstract

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.

## Key facts

- **NIH application ID:** 10805930
- **Project number:** 1R01AG085359-01
- **Recipient organization:** UNIVERSITY OF VIRGINIA
- **Principal Investigator:** HARALD W SONTHEIMER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $692,060
- **Award type:** 1
- **Project period:** 2024-06-01 → 2029-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10805930

## Citation

> US National Institutes of Health, RePORTER application 10805930, Extracellular matrix and memory impairments in Alzheimer disease (1R01AG085359-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10805930. Licensed CC0.

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