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

Abstract

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 and, 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.

BACE1 inhibitors: Current status and future directions in treating Alzheimer's disease

“…Several studies supported this hypothesis, by showing that the pharmacological and genetic RIPK1 inhibition results in the reduction of inflammatory mediators and amyloid burden, and improved memory function (Figure ). Moreover, these studies approved the role of microglia in promoting the degradation of Aβ in vitro …”

TBK1 Suppresses RIPK1-Driven Apoptosis and Inflammation during Development and in Aging

“…Aging is known to be associated with an increase in neuroinflammation, which is mediated by microglia (Conde and Streit, 2006; Perry et al, 1993). The kinase activity of RIPK1 plays a central role in mediating neuroinflammation by promoting the activation of microglia in multiple neurodegenerative diseases including ALS, AD and multiple sclerosis (MS) (Caccamo et al, 2017; Ito et al, 2016; Ofengeim et al, 2015; Ofengeim et al, 2017). RIPK1 is suppressed by inhibitory phosphorylations mediated directly by TAK1 and by the kinases activated by TAK1, including MK2 and IKKs (Dondelinger et al, 2015; Geng et al, 2017; Jaco et al, 2017; Menon et al, 2017).…”

“…This regulated necrosis is mediated by the activation of RIPK1 and subsequent activation of RIPK3 which in turn phosphorylates MLKL (Weinlich et al, 2017). Although necroptosis has been implicated in mediating the pathology of neurodegenerative diseases including ALS, AD and MS (Ito et al, 2016; Ofengeim et al, 2015; Ofengeim et al, 2017), a corresponding role for RDA in mediating these diseases has yet to be demonstrated. Furthermore, the molecular mechanisms of age-dependent activation of RIPK1 contributing to neurodegeneration in the human central nervous system (CNS) remain unclear.…”

The emerging roles of protein homeostasis‐governing pathways in Alzheimer's disease

“…At present, the inhibitors of RIPK1, such as Necrostatin‐1, display efficacy against multiple diseases, including Alzheimer's disease, immune‐dependent hepatitis, and glaucoma (Do, Sul, Jang, Kang, & Kim, 2017; Le Cann, Delehouzé, Leverrier‐Penna, Filliol, & Comte, 2017; Ofengeim, Mazzitelli, Ito, DeWitt, & Mifflin, 2017). In particular, the administration of RIPK1 inhibitors significantly decreases amyloid burden and cognitive defects among transgenic mice, suggesting its potential for future clinical development (Ofengeim et al., 2017). …”