Our proposed study will be focused on characterizing and developing a novel positron emission tomography (PET) imaging probe of Alzheimer's disease (AD) by probing necroptosis underlying AD through molecular imaging that can be utilized in animals and potentially humans. Specifically, necroptosis is a complex and regulated caspase-independent cell death mechanism mediated by various protein members, e.g. receptor-interacting protein kinase 1 (RIP1 or RIPK1) involving inflammation. Notably, RIPK1 is up-regulated by microglial cells in
human AD brains and mediates a disease-associated microglial response (DAM) in AD, which is related to an inflammatory response and a
reduction in phagocytic activity. Interestingly, down-regulation of RIPK1, by both pharmacological and genetic means, reduced amyloid
pathology, corrected altered inflammatory changes, and attenuated memory deficits in the APP/PS1 transgenic mouse model and promoted microglial degradation of Aβ in a cell model. Thus, RIPK1 is an important therapeutic target for both understanding and treatment of AD.