Autolysosomal acidification impairment as a mediator for TNFR1 induced neuronal necroptosis in Alzheimer's disease

Neuronal necroptosis-an emerging form of regulated cell death associated with neuroinflammatory signaling:Alzheimer's disease(AD)is characterized by the presence of extracellular amyloid-β(Aβ)plaques and intracellular tau neurofibrillary tangles as well as progressive neuronal loss.Recent evidence has suggested that prolonged neuroinflammation with increased levels of cytokines,arising from neuronal injury,innate immune responses from glial cells,and peripheral inflammation,leads to neuronal death and AD progression.Neuronal necroptosis is an emerging form of regulated cell death associated with neuroinflammatory signaling.Necroptosis typically occurs in response to sustained inflammation while apoptosis facilitates normal turnover of cellular contents important for growth and development.By combining features of apoptosis and necrosis,necroptosis has been proposed to constitute a more comprehensive mechanistic explanation for neurodegeneration,which is less likely to occur by the immunologically silent apoptotic cell death or by the acute occurrence of necrosis after cellular stress(Jayaraman and Reynolds,2022).