Elucidating the role of microglial Beta-hexosaminidase in microglial regulation of perineuronal nets in homeostasis and Alzheimer's disease

Project Summary The progressive cognitive decline observed in Alzheimer's Disease (AD) is linked to synaptic dysfunction and the degradation of perineuronal nets (PNNs), which are critical for neuronal protection, synaptic stability, and plasticity. Interestingly, the role of microglia, the central nervous system's resident immune cells, extends beyond their well-known involvement in neuroinflammation to include the maintenance of PNN integrity. Recent findings from our lab have revealed that β-hexosaminidase, a crucial lysosomal enzyme, is exclusively expressed in and secreted by microglia. β-hexosaminidase is critical in maintaining normal neuronal function and may also be involved in the regulation of PNNs. This research proposal aims to dissect the functional implications of microglial β-hexosaminidase on PNN regulation under normal and AD-associated conditions. In the first aim, we will explore the role of β-hexosaminidase in homeostatic PNN regulation by modulating its levels in the mouse brain. Through a combination of enzyme inhibition, microglial cell replacement, and recombinant protein infusion strategies, we aim to delineate the contribution of β-hexosaminidase to normal PNN architecture. The second aim is designed to investigate whether β-hexosaminidase is implicated in the early-stage loss of PNNs and gene expression changes in parvalbumin-positive neurons preceding their loss, both hallmarks of AD pathology. By employing a mouse model of Alzheimer's disease (5xFAD) and replacing native microglia with β-hexosaminidase-deficient myeloid cells, we will assess the impact of diminished β- hexosaminidase activity on PNN preservation and neuronal health during disease progression. Given its unique position at the nexus of microglial function and neuronal health, β-hexosaminidase represents a novel therapeutic target whose manipulation could offer significant benefits in AD. This project will advance our understanding of neurodegenerative disease research by highlighting the therapeutic potential of targeting microglial enzymes for the preservation of critical neuronal structures. Through innovative methodological approaches and a focus on the complex role of microglia in neurodegeneration, this proposal aims to bridge significant knowledge gaps and offer novel insights into the mechanisms of AD pathology. Ultimately, the findings from this study could broaden our understanding of the complex interplay between microglia, neurons, and the extracellular matrix in the brain, paving the way for the development of new glia-targeted therapies and expanding our repertoire of potential interventions in AD.