2. Academic Validation
  3. Inhibition of Smad3 in macrophages promotes Aβ efflux from the brain and thereby ameliorates Alzheimer's pathology

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

  • Brain Behav Immun. 2021 Jul;95:154-167. doi: 10.1016/j.bbi.2021.03.013.
Lu Xu 1,  Cai-Long Pan 1,  Xiang-Hui Wu 2,  Jing-Jing Song 2,  Ping Meng 3,  Lei Li 2,  Li Wang 4,  Zhiren Zhang 5,  Zhi-Yuan Zhang 6
Affiliations

Affiliations

  • 1 School of Basic Medical Sciences, Nanjing Medical University, Nanjing 211166, China; The Key Laboratory of Antibody Technique of Ministry of Health, Nanjing Medical University, Nanjing 211166, China.
  • 2 School of Basic Medical Sciences, Nanjing Medical University, Nanjing 211166, China.
  • 3 School of Basic Medical Sciences, Nanjing Medical University, Nanjing 211166, China; Department of Pathology, Zhongda Hospital, Southeast University, Nanjing 210009, China.
  • 4 Department of Hygiene Analysis and Detection, School of Public Health, Nanjing Medical University, Nanjing 211166, China.
  • 5 Institute of Immunology, Army Medical University, 30 Gaotanyan Main Street, Chongqing 400038, China.
  • 6 School of Basic Medical Sciences, Nanjing Medical University, Nanjing 211166, China; The Key Laboratory of Antibody Technique of Ministry of Health, Nanjing Medical University, Nanjing 211166, China; Department of Neurology, Sir Run Run Hospital, Nanjing Medical University, Nanjing 211166, China. Electronic address: zzy@njmu.edu.cn.
PMID: 33737172 DOI: 10.1016/j.bbi.2021.03.013
Abstract

Impaired Amyloid-β (Aβ) clearance is believed to be a primary cause of Alzheimer's disease (AD), and peripheral abnormalities in Aβ 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 Aβ. Then, manipulating the SMAD3 signaling regulated macrophage phagocytosis of Aβ and induced switch of macrophage inflammatory phenotypes in our cell cultures. In our mouse models, flag-tagged or fluorescent-dye conjugated Aβ was injected into the lateral ventricles or tail veins, and traced. Interestingly, blocking SMAD3 signaling efficiently increased Aβ clearance by macrophages, reduced Aβ in the periphery and thereby enhanced Aβ efflux from the brain. Moreover, in our APP/PS1 transgenic AD model mice, SMAD3 inhibition significantly attenuated Aβ deposition and neuroinflammation, and ameliorated cognitive deficits, probably by enhancing the peripheral clearance of Aβ. In conclusion, enhancing Aβ 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.

Keywords

Alzheimer's disease; Aβ efflux; Macrophage phagocytosis; Smad3 signaling; peripheral sink of Aβ.

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