Enriched environment requires remodeling of hippocampal perineuronal nets to trigger memory improvement in Alzheimer’s mouse model

Alzheimer’s disease (AD) is a major neurodegenerative disorder influenced by both genetic and environmental factors. Engaging in mentally stimulating activities is believed to reduce cognitive decline by establishing a cognitive reserve, though the underlying neurobiological mechanisms remain elusive. In this study, we explore the role of parvalbumin-expressing inhibitory neurons (PV) and their associated perineuronal nets (PNN) in cognitive deficits observed in AD. Using the Tg2576 mouse model, we demonstrate that 10 days of exposure to an enriched environment (EE) significantly restores spatial and social memory, accompanied by an increase in PV and PV/PNN cell populations in the hippocampus. Notably, preventing PV/PNN remodeling in the CA1 region during EE abolishes the spatial memory improvements, whereas localized neuregulin-1 (NRG1) injections induce PV/PNN remodeling and restore memory function. These findings suggest that hippocampal PV/PNN remodeling is essential for the cognitive benefits of EE in AD, highlighting this neuronal population as a critical substrate for cognitive reserve. This study provides new insights into the mechanisms by which environmental factors may mitigate cognitive decline in AD, offering potential avenues for therapeutic interventions. Highlights: 10-day environmental enrichment increases PV+ and PV+/PNN+ in the hippocampus of Tg2576 mouse model of AD Blocking PV/PNN remodeling during EE prevents memory recovery in Tg2576 mice Enhancing PV/PNN remodeling with NRG1 leads to restored memory in Tg2576 mice PV/PNN remodeling in area CA1 affects spatial memory, while in CA2, it impacts social memory