Inhibition of Smad3 in macrophages promotes Aβ efflux from the brain and thereby ameliorates Alzheimer's pathology

Impaired amyloid-beta (A beta) clearance is believed to be a primary cause of Alzheimer's disease (AD), and peripheral abnormalities in A beta clearance have recently been linked to AD pathogenesis and progression. Data from recent genome-wide association studies have linked genetic risk factors associated with altered functions of more immune cells to AD pathology. Here, we first identified correlations of Smad3 signaling activation in peripheral macrophages with AD progression and phagocytosis of A. Then, manipulating the Smad3 signaling regulated macrophage phagocytosis of A beta and induced switch of macrophage inflammatory phenotypes in our cell cultures. In our mouse models, flag-tagged or fluorescent-dye conjugated A beta was injected into the lateral ventricles or tail veins, and traced. Interestingly, blocking Smad3 signaling efficiently increased A beta clearance by macrophages, reduced A beta in the periphery and thereby enhanced A beta efflux from the brain. Moreover, in our APP/PS1 transgenic AD model mice, Smad3 inhibition significantly attenuated A beta deposition and neuroinflammation, and ameliorated cognitive deficits, probably by enhancing the peripheral clearance of A. In conclusion, enhancing A beta clearance by peripheral macrophages through Smad3 inhibition attenuated AD-related pathology and cognitive deficits, which may provide a new perspective for understanding AD and finding novel therapeutic approaches.

Automated summary

Inhibition of Smad3 signaling pathway enhances peripheral macrophage clearance of A beta, thereby alleviating AD-related pathology and cognitive deficits.