RIPK 1 in Alzheimer's Disease: Research Progress Integrating Pathogenesis on Necroptosis-Related Neuroinflammation,...

Background/Objectives: Alzheimer's disease (AD) is the most common cause of dementia worldwide; however, there is incomplete understanding of AD pathogenesis, and there are few disease-modifying treatments for AD. Research has begun to demonstrate that necroptosis, which is a regulated type of cell death mediated by receptor-interacting protein kinase 1 (RIPK1), plays a significant role in neurodegeneration and neuropathology associated with AD. The purpose of this review is to summarize current research regarding the role of RIPK1 in AD and possible therapeutic uses of RIPK1 inhibitors. Methods: This study is a narrative review of the literature summarizing experimental and clinical studies on RIPK1 signaling, necroptosis, neuroinflammation, and blood-brain barrier (BBB) dysfunction in AD. Results: The cumulative evidence demonstrates that RIPK1 activation associates with common AD pathways and particularly increases the severity of amyloid-β (Aβ) and tau pathology; promotes microglial activation; decreases the integrity of the BBB; and increases neuroinflammatory signaling in AD. Preclinical studies have shown that inhibiting RIPK1 genetically or pharmacologically in preclinical models decreased the extent of neurodegeneration and the rate of cognitive decline. Conclusions: RIPK1 is a key molecular link between necroptosis and neuroinflammation in AD. While the preclinical data are encouraging, further clinical research will be necessary to investigate RIPK1 changes in the brain, which may help better understand AD and establish the safety and effectiveness of potential therapeutic RIPK1 inhibitors in AD.