RIPK1 mediates a disease-associated microglial response in Alzheimer's disease
Department of Molecular, Cell and Cancer Biology; UMass Metabolic Network
Biochemistry | Cell Biology | Cellular and Molecular Physiology | Molecular Biology
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 Abeta 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.
Alzheimer’s disease, RIP1, RIPK1, inflammation, microglia
DOI of Published Version
Proc Natl Acad Sci U S A. 2017 Oct 10;114(41):E8788-E8797. doi: 10.1073/pnas.1714175114. Epub 2017 Sep 13. Link to article on publisher's site
Proceedings of the National Academy of Sciences of the United States of America
Ofengeim, Dimitry; Kelliher, Michelle A.; and Yuan, Junying, "RIPK1 mediates a disease-associated microglial response in Alzheimer's disease" (2017). UMass Metabolic Network Publications. 159.