Alzheimer’s disease (AD) is associated with dysfunction of microglia, which are macrophage-like cells of the central nervous system. Researchers recently identified a subtype of disease-associated microglia (DAM) that may modulate AD pathogenesis, but the underlying mechanisms are still unclear.
Researchers investigated the role of RIPK1—a kinase that is highly expressed in the microglial cells of AD brains—in AD pathogenesis using an amyloid precursor protein/presenilin 1 transgenic mouse model of AD.
The authors found that pharmacological or genetic inhibition of RIPK1 led to reduced amyloid burden and lower levels of inflammatory cytokines. Inhibiting RIPK1 also reduced behavioral deficits and improved memory function in the transgenic mice.
The authors found that the kinase activity of RIPK1 plays a role in upregulating microglial expression of Cst7, which encodes a cathepsin inhibitor called cystatin F. RIPK1-dependent induction of Cst7 leads to impairments in the lysosomal pathway. RIPK1 inhibition restores normal levels of Cst7 and appears to inhibit the DAM response and promote microglial degradation of amyloid-β in vitro.
The results indicate a mechanism by which RIPK1 might mediate the induction of a DAM state that reduces microglial phagocytic activity and promotes an inflammatory response, and the authors suggest that RIPK1 could serve as a therapeutic target for AD.
http://www.pnas.org/content/early/2017/09/12/1714175114
Microglial response in Alzheimer's disease
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