Abstract

Alzheimer's disease (AD) is a major adult-onset neurodegenerative condition with no available treatment. Compelling reports point amyloid-beta (A beta) as the main etiologic agent that triggers AD. Although there is extensive evidence of detrimental crosstalk between AP and microglia that contributes to neuroinflammation in AD, the exact mechanism leading to neuron death remains unknown. Using postmortem human AD brain tissue, we show that A beta pathology is associated with the necroptosis effector pMLKL. Moreover, we found that the burden of A beta oligomers (A beta o) correlates with the expression of key markers of necroptosis activation. Additionally, inhibition of necroptosis by pharmacological or genetic means, reduce neurodegeneration and memory impairment triggered by A beta o in mice. Since microglial activation is emerging as a central driver for AD pathogenesis, we then tested the contribution of microglia to the mechanism of A beta o-mediated necroptosis activation in neurons. Using an in vitro model, we show that conditioned medium from A beta o-stimulated microglia elicited necroptosis in neurons through activation of TNF-alpha signaling, triggering extensive neurodegeneration. Notably, necroptosis inhibition provided significant neuronal protection. Together, these findings suggest that A beta o-mediated microglia stimulation in AD contributes to necroptosis activation in neurons and neurodegeneration. As necroptosis is a druggable degenerative mechanism, our findings might have important therapeutic implications to prevent the progression of AD.