Age-Dependent Sex Differences in Perineuronal Nets in an APP Mouse Model of Alzheimer’s Disease Are Brain Region-Specific

Alzheimer’s disease (AD) is the most common form of dementia, which disproportionately affects women. AD symptoms include progressive memory loss associated with amyloid-β (Aβ) plaques and dismantled synaptic mechanisms. Perineuronal nets (PNNs) are important components of the extracellular matrix with a critical role in synaptic stabilisation and have been shown to be influenced by microglia, which enter an activated state during AD. This study aimed to investigate whether sex differences affected the density of PNNs alongside the labelling of microglia and Aβ plaques density.We performed neurochemistry experiments using acute brain slices from both sexes of the APP(NL-F/NL-F) mouse model of AD, aged-matched (2–5 and 12–16 months) to wild-type mice, combined with a weighted gene co-expression network analysis (WGCNA). The lateral entorhinal cortex (LEC) and hippocampal CA1, which are vulnerable during early AD pathology, were investigated and compared to the presubiculum (PRS), a region unscathed by AD pathology. The highest density of PNNs was found in the LEC and PRS regions of aged APP(NL-F/NL-F) mice with a region-specific sex differences. Analysis of the CA1 region using multiplex-fluorescent images from aged APP(NL-F/NL-F) mice showed regions of dense Aβ plaques near clusters of CD68, indicative of activated microglia and PNNs. This was consistent with the results of WGCNA performed on normalised data on microglial cells isolated from age-matched, late-stage male and female wild-type and APP knock-in mice, which revealed one microglial module that showed differential expression associated with tissue, age, genotype, and sex, which showed enrichment for fc-receptor-mediated phagocytosis. Our data are consistent with the hypothesis that sex-related differences contribute to a disrupted interaction between PNNs and microglia in specific brain regions associated with AD pathogenesis.