RIPK1 mediates a disease-associated microglial response in Alzheimer’s disease

Significance Dysfunction of microglia plays a fundamental role in the pathogenesis of Alzheimer’s disease (AD), the most common form of dementia. However, there is a lack of knowledge about targets that can be safely manipulated for modulating microglia for the treatment of AD. The presence of a unique subtype of disease-associated microglia (DAM) has recently been implicated in mediating pathogenesis of AD. However, the mechanism that promotes the development of DAM is unclear, nor is it known how DAM may modulate the progression of AD. This study demonstrates that RIPK1-dependent transcription promotes DAM and lysosomal defects to mediate the accumulation of amyloid plaques in AD. Thus, targeting RIPK1 may provide an important therapeutic strategy for the treatment of AD. Dysfunction of microglia is known to play an important role in Alzheimer’s disease (AD). Here, we investigated the role of RIPK1 in microglia mediating the pathogenesis of AD. RIPK1 is highly expressed by microglial cells in human AD brains. Using the amyloid precursor protein (APP)/presenilin 1 (PS1) transgenic mouse model, we found that inhibition of RIPK1, using both pharmacological and genetic means, reduced amyloid burden, the levels of inflammatory cytokines, and memory deficits. Furthermore, inhibition of RIPK1 promoted microglial degradation of Aβ in vitro. We characterized the transcriptional profiles of adult microglia from APP/PS1 mice and identified a role for RIPK1 in regulating the microglial expression of CH25H and Cst7, a marker for disease-associated microglia (DAM), which encodes an endosomal/lysosomal cathepsin inhibitor named Cystatin F. We present evidence that RIPK1-mediated induction of Cst7 leads to an impairment in the lysosomal pathway. These data suggest that RIPK1 may mediate a critical checkpoint in the transition to the DAM state. Together, our study highlights a non-cell death mechanism by which the activation of RIPK1 mediates the induction of a DAM phenotype, including an inflammatory response and a reduction in phagocytic activity, and connects RIPK1-mediated transcription in microglia to the etiology of AD. Our results support that RIPK1 is an important therapeutic target for the treatment of AD.

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