Degradation of perineuronal nets in hippocampal CA2 explains the loss of social cognition memory in Alzheimer's disease

Abstract

INTRODUCTION: Loss of social cognition memory impairs Alzheimer's disease (AD) patients to recognize family members, friends, and caregivers. We investigate the role of perineuronal nets (PNNs), specialized coats of extracellular matrix around hippocampal CA2 neurons in AD-associated social memory impairments. METHODS: We utilized 5XFAD mouse model of AD and employed immunohistochemistry, microscopy, bulk RNA-sequencing, animal behavior, gene-knockout, and drug-treatment approaches. RESULTS: AD mice showed profound disruption of CA2 PNNs with concomitant impairment of social cognition memory. Genetic or enzymatic CA2 PNN disruption in wild-type mice mimicked these impairments. Transcriptomic analysis shows upregulation of PNN-cleaving matrix metalloproteinases (MMP) in AD mice causing disequilibrium of PNN synthesis and remodeling. Chronic inhibition of MMPs retains CA2 PNN and delays social memory impairments in 5XFAD mice. DISCUSSION: AD-associated social memory impairments are caused by loss of CA2 PNNs. Inhibition of PNN proteolysis by MMPs preserves social memory, suggesting PNN as a promising therapeutic target. Highlights: Perineuronal nets (PNNs) are disrupted in the CA2 area of the hippocampus in 5XFAD Alzheimer's disease (AD) mice at 6 months of age and beyond. Social memory deficits in 5XFAD mice coincide with the disruption of CA2 PNNs and PNN loss alone is sufficient to cause loss of social memory. Bulk RNA sequencing of hippocampal CA2 tissue reveals alterations in PNN remodeling enzymes. Inhibition of matrix metalloproteinase (MMP) activity with GM6001 prevents PNN disruption and protects against social memory deficits in the 5XFAD AD mouse model.