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oai:riuma.uma.es:10630/396522026-02-03T11:17:58Zcom_10630_2254col_10630_37953

00925njm 22002777a 4500 dc Salvadores, Natalia author Moreno-González, Inés author Gámez, Nazaret author Quiroz, Gabriel author Vegas-Gómez, Laura author Escandón, Marcelo author Jiménez, Sebastián author Vitorica Ferrández, Javier author Gutiérrez-Pérez, Antonia author Soto, Claudio author Court, Felipe A. author 2022-03-09 Alzheimer’s disease (AD) is a major adult-onset neurodegenerative condition with no available treatment. Compelling reports point amyloid-β (Aβ) as the main etiologic agent that triggers AD. Although there is extensive evidence of detrimental crosstalk between Aβ 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 Aβ pathology is associated with the necroptosis effector pMLKL. Moreover, we found that the burden of Aβ oligomers (Aβo) 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 Aβo 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 Aβo-mediated necroptosis activation in neurons. Using an in vitro model, we show that conditioned medium from Aβo-stimulated microglia elicited necroptosis in neurons through activation of TNF-α signaling, triggering extensive neurodegeneration. Notably, necroptosis inhibition provided significant neuronal protection. Together, these findings suggest that Aβo-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. Salvadores, N., Moreno-Gonzalez, I., Gamez, N. et al. Aβ oligomers trigger necroptosis-mediated neurodegeneration via microglia activation in Alzheimer’s disease. acta neuropathol commun 10, 31 (2022). https://doi.org/10.1186/s40478-022-01332-9 https://hdl.handle.net/10630/39652 10.1186/s40478-022-01332-9 Alzheimer, Enfermedad de Sistema nervioso - Degeneración Neuroglia Amiloide Muerte celular Aβ oligomers trigger necroptosis-mediated neurodegeneration via microglia activation in Alzheimer’s disease.