Aβ oligomers trigger necroptosis-mediated neurodegeneration via microglia activation in Alzheimer's disease.
Natalia SalvadoresInes Moreno-GonzalezNazaret GamezGabriel QuirozLaura Vegas-GomezMarcela EscandónSebastian JimenezJavier VitoricaAntonia GutierrezClaudio SotoFelipe A CourtPublished in: Acta neuropathologica communications (2022)
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.
Keyphrases
- inflammatory response
- neuropathic pain
- spinal cord
- endothelial cells
- lipopolysaccharide induced
- traumatic brain injury
- type diabetes
- poor prognosis
- emergency department
- metabolic syndrome
- spinal cord injury
- lps induced
- genome wide
- long non coding rna
- binding protein
- cerebral ischemia
- working memory
- smoking cessation
- copy number
- induced pluripotent stem cells
- replacement therapy