Age‐Dependent Changes in Perineuronal Nets and Associated Parvalbumin Interneurons in the 5xFAD Amyloidosis Mouse Model

Abstract

AbstractBackgroundPerineuronal nets (PNNs) are extracellular matrix structures that surround neurons and proximal dendrites and regulate synaptic transmission, plasticity, and several facets of memory. PNNs are commonly associated with parvalbumin‐positive (PV+) fast‐spiking interneurons which are hypothesized to play physiological roles in memory and cognition. Despite a growing literature related to PNNs and PV+ neurons’ roles in synaptic maintenance and memory, much remains unknown regarding how these structures are affected in neurodegenerative diseases such as Alzheimer’s Disease (AD). In this study, we used the 5xFAD amyloidosis mouse model to investigate how AD‐like pathology affects PNNs and PV+ neuronsMethodUsing immunofluorescence microscopy, we stained 5xFAD and Wild Type (WT) mice at 1.8, 3, 6, and 10 months of age. We stained for PV+ neurons (using anti‐PV antibody), PNNs (using a WFA antibody), and for Amyloid‐Beta (Aβ) plaques (using a 4G8 antibody). Images were then processed using ImageJ to quantify the presence of PV+ neurons, PNNs, and the association between them in several regions of interest across genotypes and age groups.ResultWe found that PNNs, but not PV+ neurons, are significantly depleted in the anterior cortex, posterior cortex, and subiculum of the 5XFAD mice in early amyloidosis (3‐6 month old 5XFAD mice). Furthermore, analyses investigating the co‐localization of PNNs and PV+ neurons in these regions found that PNNs were depleted surrounding PV+ neurons in an age‐dependent manner in the 5XFAD mice compared to WT. Specifically, in early amyloidosis (3‐6 months) there was a general depletion of PNNs, but in later amyloidosis (6 ‐10 months) the depletion of PNNs was preferentially surrounding PV+ neurons. Finally, assessing the relationship between Aβ plaque proximity and the co‐localization between PNNs and PV+ neurons revealed that PNNs closer to Aβ plaques were more likely to be associated with PV+ neuronsConclusionCollectively, these findings may indicate the time‐dependent impact of Aβ pathology on PNNs, both in general and specifically surrounding PV+ neurons. Our ongoing studies will further characterize PNN and PV changes across a wider age spectrum.