Contribution of cGAS-P2X2 crosstalk on synaptic failure and mitochondrial dysfunction induced by β-amyloid oligomers

One of the primary pathological factors implicated in Alzheimer's disease (AD) is the beta-amyloid peptide (Aβ), known for its various toxic effects including decreased cytosolic ATP levels and elevated intracellular calcium. Our laboratory's research has revealed that Aβ treatments induce alterations in mitochondrial morphology and dynamics in animal models of AD, leading to increased ROS generation and potential leakage of mitochondrial elements like mitochondrial DNA (mtDNA) into the cytoplasm. MtDNA can activate the inflammatory response via cyclic GMP-AMP synthase (cGAS), triggering proinflammatory cytokine production. Our study aimed to investigate Aβ's impact on the cGAS pathway using SH-SY5Y neuronally differentiated cells and primary mouse hippocampal neurons. Interestingly, we found cGAS predominantly localized in neurons rather than glial cells, primarily within the nucleus. Chronic Aβ treatments induced changes in cGAS distribution and increased IL-6 and TNF-α production in a time-dependent manner, potentially modulating cGAS activity and contributing to the proinflammatory milieu in neurons. Additionally, we evaluated the expression of the P2X2 receptor in postmortem brain samples from Alzheimer's disease patients (Braak I-VI stages). We observed a significant increase in P2X2 levels in samples from patients classified in Braak stages V-VI. We further investigated these findings in synaptic fractions from the prefrontal cortex of AD patients and observed a nearly 200% increase in presynaptic P2X2 in Braak II-III/V-VI patients. Our study highlights the role of β-amyloid oligomers in modulating the cGAS pathway and P2X2 receptor overexpression, shedding light on their contribution to synaptic dysfunction in Alzheimer's disease.