The adhesion and migration of microglia to β-amyloid (Aβ) is decreased with aging and inhibited by Nogo/NgR pathway

Background: Alzheimer's disease is characterized by progressive accumulation of beta-amyloid (A beta)-containing amyloid plaques, and microglia play a critical role in internalization and degradation of A beta. Our previous research confirmed that Nogo-66 binding to Nogo receptors (NgR) expressed on microglia inhibits cell adhesion and migration in vitro. Methods: The adhesion and migration of microglia isolated from WT and APP/PS1 mice from different ages were measured by adhesion assays and transwells. After NEP1-40 (a competitive antagonist of Nogo/NgR pathway) was intracerebroventricularly administered via mini-osmotic pumps for 2 months in APP/PS1 transgenic mice, microglial recruitment toward A beta deposits and CD36 expression were determined. Results: In this paper, we found that aging led to a reduction of microglia adhesion and migration to fA beta(1-42) in WT and APP/PS1 mice. The adhesion and migration of microglia to fA beta(1-42) were downregulated by the Nogo, which was mediated by NgR, and the increased inhibitory effects of the Nogo could be observed in aged mice. Moreover, Rho GTPases contributed to the effects of the Nogo on adhesion and migration of microglia to fA beta(1-42) by regulating cytoskeleton arrangement. Furthermore, blocking the Nogo/NgR pathway enhanced recruitment of microglia toward AP deposits and expression of CD36 in APP/PS1 mice. Conclusion: Taken together, Nogo/NgR pathway could take part in A beta pathology in AD by modulating microglial adhesion and migration to A beta and the Nogo/NgR pathway might be an important target for treating AD.