Nogo receptor impairs the clearance of fibril amyloid-β by microglia and accelerates Alzheimer's-like disease progression

Alzheimer's disease (AD) is characterized by the progressive accumulation of beta-amyloid (A beta)-containing amyloid plaques, and microglia play a critical role in mediating A beta clearance. Mounting evidence has confirmed that the ability of microglia in clearing A beta decreased with aging and AD progress, but the underlying mechanisms are unclear. Previously, we have demonstrated that Nogo receptor (NgR), a receptor for three axon growth inhibitors associated with myelin, can decrease adhesion and migration of microglia to fibrils A beta with aging. However, whether NgR expressed on microglia affect microglia phagocytosis of fibrils A beta with aging remains unclear. Here, we found that aged but not young microglia showed increased NgR expression and decreased A beta phagocytosis in APP/PS1 transgenic mice. NgR knockdown APP/PS1 mice showed simultaneous reduced amyloid burden and improved spatial learning and memory, which were associated with increased A beta clearance. Importantly, Nogo-P4, an agonist of NgR, enhanced the protein level of p-Smad2/3, leading to a significant transcriptional inhibition of CD36 gene expression, which in turn decreased the microglial phagocytosis of A beta. Moreover, ROCK accounted for Nogo-P4-induced activation of Smad2/3 signaling. Finally, the decreasing effect of NgR on microglial A beta uptake was confirmed in a mouse model of intra-hippocampal fA beta injection. Our findings suggest that NgR may play an important role in the regulation of A beta homeostasis, and has potential as a therapeutic target for AD.

Automated summary

The study shows that NgR plays a crucial role in microglial clearance of Aβ, with increased NgR expression in aged microglia leading to decreased Aβ phagocytosis. Knockdown of NgR reduces amyloid burden and improves cognitive function in an AD mouse model. Moreover, NgR activation inhibits CD36 gene expression through Smad2/3 signaling, thereby reducing microglial Aβ uptake.