La neuroinfiammazione nella malattia di Alzheimer

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by amyloid-β plaques and tau protein aggregates. Recent studies indicate that inflammation, particularly microglial activation, plays a crucial role in AD progression. In this study, we investigate the role of microglia in an AD mouse model harboring PS2 and APP mutations, focusing on the impact of the ATP-gated P2X7 receptor (P2X7R) on microglial activation and neuroinflammation. Our findings show that microglial activation occurs early in the AD mouse model, even before amyloid plaque deposition, and is associated with increased phagocytic activity and morphological changes. We generated a triple transgenic mouse line lacking P2X7R (AD-P2X7RKO) and found that P2X7R knockout restores normal microglial morphology and reduces phagocytic activity at early disease stages. Notably, P2X7R ablation also prevents the degradation of perineuronal nets (PNNs), extracellular matrix structures critical for maintaining inhibitory synapses, through the downregulation of matrix metalloproteinase-9 (MMP9). Overall, our study highlights two key mechanisms by which microglia contribute to neuronal hyperexcitability in the AD model: selective pruning of synapses and remodeling of PNNs. The P2X7R appears to play a central role in these processes, suggesting it could be a promising therapeutic target, particularly in the early stages of AD.