Summary: Researchers at the University of Virginia have identified a structural cause for the heartbreaking loss of recognition seen in many people with Alzheimer’s disease. They found that degradation of perineuronal nets — mesh-like extracellular structures that wrap neurons — in the hippocampal CA2 region disrupts social memory. In mouse models, loss of these nets erased recognition of familiar individuals while leaving object memory intact. Treating the mice with matrix metalloproteinase (MMP) inhibitors preserved the nets and protected social memory, revealing a potential therapeutic strategy that is independent of amyloid pathology.
This discovery highlights perineuronal nets (PNNs) and their stability as a promising target for interventions aimed at preventing or delaying the specific memory decline that causes Alzheimer’s patients to forget loved ones and caregivers.
Key Facts
- Memory Mechanism: Loss of social memory in Alzheimer’s is linked to degradation of perineuronal nets that surround neurons, especially in hippocampal CA2.
- Drug Potential: In mouse models, MMP inhibitors prevented PNN breakdown and helped preserve recognition of familiar individuals.
- New Target: The mechanism appears to operate independently of amyloid plaque accumulation, offering an alternative therapeutic pathway.
Source: University of Virginia
The emotional weight of forgotten faces
One of the most distressing moments for families affected by Alzheimer’s is when a person no longer recognizes close relatives, friends or caregivers. New research from the University of Virginia School of Medicine, led by Harald Sontheimer, PhD, and graduate student Lata Chaunsali, sheds light on why this specific form of memory loss occurs and points to a possible way to prevent it.
The team discovered that perineuronal nets — specialized extracellular matrix structures that coat neurons and regulate synaptic communication — are critical for maintaining social memory. In mouse models of Alzheimer’s disease, PNNs in the hippocampal CA2 region became degraded, and the mice lost their ability to remember other mice they had met earlier. Notably, their ability to remember objects remained intact, matching clinical observations where social recognition often deteriorates before other memory types in human patients.
To test whether protecting PNNs could preserve social memory, the researchers applied inhibitors of matrix metalloproteinases (MMPs), enzymes that cleave components of the extracellular matrix. Chronic MMP inhibition in the Alzheimer’s model mice preserved CA2 PNNs and delayed the onset of social memory impairment.
“Finding a structural change that explains a specific memory loss in Alzheimer’s is very exciting,” said Sontheimer, chair of UVA’s Department of Neuroscience and a member of the UVA Brain Institute. “It points to a completely new therapeutic target, and there are already candidate drugs that can inhibit the enzymes involved.”
Alzheimer’s: a growing public health challenge
Alzheimer’s disease currently affects an estimated 55 million people worldwide, and prevalence is expected to increase significantly in the coming years. In response, UVA has created the Harrison Family Translational Research Center in Alzheimer’s and Neurodegenerative Diseases to accelerate discovery and translate laboratory findings into potential treatments.
Sontheimer’s prior work established the importance of perineuronal nets for healthy neuronal communication and memory formation. Building on that foundation, the team examined how PNN integrity relates to the social memory deficits characteristic of Alzheimer’s. Their findings indicate that disruption of CA2 PNNs is sufficient to cause social memory loss, and that preserving these nets can protect social recognition even in the presence of other disease-associated brain changes.
Co-first author Lata Chaunsali emphasized the translational potential: “When we maintained these PNNs early in the disease course in mice, their ability to remember social interactions improved. This suggests a non-traditional approach to treating or preventing aspects of Alzheimer’s disease that are currently difficult to manage.”
Sontheimer added a note of caution and perspective: while experiments demonstrate that MMP inhibitors can delay PNN degradation and preserve memory in mice, further work is needed to evaluate safety, dosing, and long-term effects before considering human trials. Importantly, the team observed that PNN loss occurred independently of amyloid and plaque pathology, strengthening the view that amyloid accumulation may not be the sole or direct cause of all Alzheimer’s-related deficits.
Findings Published
The study is published in Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association. The open-access article lists Lata Chaunsali, Jiangtao Li, Erik Fleischel, Courtney E. Prim, Izabela Kasprzak, Shan Jiang, Silky Hou, Miguel Escalante, Elise C. Cope, Michelle L. Olsen, Bhanu P. Tewari and Harald Sontheimer as authors. The researchers report no financial conflicts of interest.
Funding: The work was supported by the National Institutes of Health (grants R01AG065836, R01NS036692, and R01NS123069), The Owens Family Foundation, a Wagner fellowship, and a Double Hoo fellowship.
Key Questions Answered:
A: The study explains why people with Alzheimer’s may stop recognizing loved ones, linking this loss to degradation of perineuronal nets that support social memory.
A: Perineuronal nets — mesh-like extracellular coats around neurons, especially in the hippocampal CA2 region — are essential for maintaining social memory.
A: In mouse models, protecting PNNs by inhibiting MMPs preserved social memory, suggesting that PNN stabilization may be a viable strategy to delay specific aspects of Alzheimer’s-related memory loss.
About this research news
Author: Josh Barney
Source: University of Virginia
Contact: Josh Barney – University of Virginia
Image: The image is credited to Neuroscience News
Original Research: Open access.
“Degradation of perineuronal nets in hippocampal CA2 explains the loss of social cognition memory in Alzheimer’s disease” by Lata Chaunsali et al., published in Alzheimer’s & Dementia.
Abstract
Degradation of perineuronal nets in hippocampal CA2 explains the loss of social cognition memory in Alzheimer’s disease
INTRODUCTION
Loss of social cognition memory prevents people with Alzheimer’s disease from recognizing family members, friends, and caregivers. This study investigates the role of perineuronal nets (PNNs), specialized extracellular matrix coats around hippocampal CA2 neurons, in Alzheimer’s-associated social memory impairments.
METHODS
The researchers used the 5XFAD mouse model of Alzheimer’s disease and combined immunohistochemistry, microscopy, bulk RNA sequencing, behavioral assays, genetic manipulation, and pharmacological intervention to examine PNN integrity and its functional consequences.
RESULTS
AD model mice displayed clear disruption of CA2 PNNs alongside deficits in social memory. Genetic or enzymatic removal of CA2 PNNs in healthy mice reproduced these impairments. Transcriptomic data revealed upregulation of matrix metalloproteinases (MMPs) that cleave PNN components, creating an imbalance between PNN synthesis and remodeling. Chronic inhibition of MMPs preserved CA2 PNNs and delayed social memory loss in 5XFAD mice.
DISCUSSION
The findings indicate that Alzheimer’s-associated social memory impairment results from loss of CA2 perineuronal nets. Inhibiting PNN proteolysis by MMPs preserves social memory, identifying PNN stability as a promising and mechanistically distinct therapeutic target for preventing or slowing specific cognitive deficits in Alzheimer’s disease.