RT Journal Article
T1 Aβ oligomers trigger necroptosis-mediated neurodegeneration via microglia activation in Alzheimer's disease.
A1 Salvadores, Natalia
A1 Moreno-Gonzalez, Ines
A1 Gamez, Nazaret
A1 Quiroz, Gabriel
A1 Vegas-Gomez, Laura
A1 Escandon, Marcela
A1 Jimenez, Sebastian
A1 Vitorica, Javier
A1 Gutierrez, Antonia
A1 Soto, Claudio
A1 Court, Felipe A
K1 Alzheimer’s disease
K1 Amyloid-β oligomers
K1 Microglia
K1 Necroptosis
K1 Neurodegeneration
K1 Neuroprotection
AB 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.
PB BioMed Central Ltd.
YR 2022
FD 2022-03-09
LK http://hdl.handle.net/10668/20373
UL http://hdl.handle.net/10668/20373
LA en
NO Salvadores N, Moreno-Gonzalez I, Gamez N, Quiroz G, Vegas-Gomez L, Escandón M, et al. Aβ oligomers trigger necroptosis-mediated neurodegeneration via microglia activation in Alzheimer's disease. Acta Neuropathol Commun. 2022 Mar 9;10(1):31.
DS RISalud
RD Apr 8, 2025