Synaptic sentinels: Unveiling the role of glial cells in Alzheimer's pathogenesis

Synapse loss is a key feature of cognitive decline in Alzheimer’s disease (AD). Emerging evidence points toward the involvement of glial cells, alongside neurons, in disease progression. Understanding how glia remodel synaptic connections is crucial for understanding the onset of AD. Additionally, in the context of AD-specific risk genes, how this intricate balance is disrupted will aid in deciphering early disease mechanisms. In this study, primary glia cells were co-cultured in 3D with primary neurons pre-treated with pharmacological modulators targeting amyloid precursor protein (APP) processing. Glial morphology, activation state, and effect on neighboring synaptic distribution and neuronal connectivity were assessed using immunocytochemistry, calcium dynamics, and multielectrode array (MEA) recordings. Synaptoneurosomes isolated from pre-treated neurons were characterized for distinct lipid markers. Synaptosome engulfment by glial cells was visualized by Synaptophagy assays. The extent of glial cell activation was examined using an ELISA panel for inflammatory markers. Our findings indicate that modulating APP proteolytic cleavage has distinct effects on network activity, particularly impacting the balance between synaptic excitation and inhibition via the presynapse. In our co-culture systems, glial cells adjacent to dysfunctional synapses exhibited differential responses compared to those near functional connections. Also, microglia and astroglia show differences in the engulfment of synapses in an APP metabolite-specific manner. Our studies provide insights into the molecular and cellular changes underlying synaptic dysfunction/degeneration during the onset and progression of AD. This approach holds promise for uncovering the role of APP processing and glia-associated risk factors in AD pathogenesis and identifying potential therapeutic targets.