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Artículo
Aβ oligomers trigger necroptosis-mediated neurodegeneration via microglia activation in Alzheimer’s disease
Autor/es | Salvadores, Natalia
Moreno González, Inés Gámez, Nazaret Quiroz, Gabriel Vegas Gómez, Laura Escandón, Marcela Jiménez Muñoz, Sebastián Vitorica Ferrández, Francisco Javier Gutiérrez Pérez, Antonia Soto, Claudio Court, Felipe A. |
Departamento | Universidad de Sevilla. Departamento de Bioquímica y Biología Molecular |
Fecha de publicación | 2022 |
Fecha de depósito | 2022-03-24 |
Publicado en |
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Resumen | 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 ... 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. |
Agencias financiadoras | Junta de Andalucía Ministerio de Ciencia e Innovación (MICIN). España |
Identificador del proyecto | US-1262734 (JV), UMA18-FEDERJA-211 (AG), UMA20-FED‑ ERJA-104 (I-MG) and P18-RT-2233 (to AG)
PID2019-107090RA-I00 |
Cita | Salvadores, N., Moreno González, I., Gámez, N., Quiroz, G., Vegas Gómez, L., Escandón, M.,...,Court, F.A. (2022). Aβ oligomers trigger necroptosis-mediated neurodegeneration via microglia activation in Alzheimer’s disease. Acta Neuropathologica Communications, 10, -31. |
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