Mouse Bone Marrow-derived Microglia-like Cells Secrete Transforming Growth Factor-β1 and Promote Microglial Aβ Phagocytosis and Reduction of Brain Aβ. (1st July 2020)

• Record Type: Journal Article
• Authors: Kuroda, Eriko; Nishimura, Kaneyasu; Kawanishi, Shohei; Sueyoshi, Mari; Ueno, Fumitaka; Toji, Yumiko; Abo, Naoko; Konishi, Toko; Harada, Koki; Satake, Shiho; Shima, Chiaki; Toda, Yuki; Kitamura, Yoshihisa; Shimohama, Shun; Ashihara, Eishi; Takata, Kazuyuki
• Is Part Of: Neuroscience. Volume 438(2020)
• Page Start: 217
• Page End: 228
• Publication Date: 2020-07-01
• Subjects: AD Alzheimer's disease -- Aβ amyloid-β -- BM bone marrow -- BMDML bone marrow-derived microglia-like -- CSF-1 colony-stimulated factor-1 -- ELISA enzyme-linked immunosorbent assay -- FBS fetal bovine serum -- Iba1 ionized calcium-binding adapter molecule 1 -- PFA paraformaldehyde -- PBS phosphate-buffered saline -- SEM standard error of the mean -- TGF-β1 transforming growth factor-β1 -- TGF-βR1 TGF-β receptor type 1; Alzheimer's disease -- amyloid-β -- microglia -- bone marrow-derived microglia-like cells -- transforming growth factor-β1 -- Smad2/3; Neurochemistry -- Periodicals; Neurophysiology -- Periodicals; Neurology -- Periodicals; Neurochimie -- Périodiques; Neurophysiologie -- Périodiques; Neurochemistry; Neurophysiology; Electronic journals; Periodicals; Electronic journals; 612.8
• DOI: 10.1016/j.neuroscience.2020.05.004
• Languages: English
• ISSNs: 0306-4522

Abstract

Graphical abstract: Highlights: Bone marrow-derived microglia-like (BMDML) cells secrete TGF-β1. TGF-β1 secreted from BMDML cells promotes microglial Aβ phagocytosis via TGF-β1R. TGF-β1 signaling contributes to Aβ clearance in vivo after BMDML cell transplantation. Abstract: Accumulation of amyloid-β (Aβ) in brain tissue contributes to the pathophysiology of Alzheimer's disease (AD). We recently reported that intrahippocampal transplantation of mouse bone marrow-derived microglia-like (BMDML) cells suppresses brain amyloid pathology and cognitive impairment in a mouse model of AD. How these transplanted cells interact with resident microglia remains unknown. In the present study, we evaluated the effects of cytokines secreted from mouse BMDML cells on cultured mouse microglia. Conditioned medium from BMDML cells increased microglial Aβ phagocytosis. High levels of transforming growth factor-β1 (TGF-β1) were present in the conditioned medium, and BMDML cells and microglia expressed Tgf-β1 mRNA and TGF-β receptor type 1 (TGF-βR1) protein, respectively. BMDML conditioned medium also induced microglial Smad2/3 phosphorylation. A TGF-βR1 inhibitor suppressed Smad2/3 phosphorylation and promotion of microglial Aβ phagocytosis induced by conditioned medium. Recombinant mouse TGF-β1 similarly increased microglial Aβ phagocytosis and induced Smad2/3 phosphorylation, which were suppressed by the TGF-βR1 inhibitor. Brain TGF-β1 levels and resident microglial TGF-β1R expression were increased by intrahippocampal injection of BMDML cells in a mouse model of AD. Cotreatment with the TGF-βR1 inhibitor suppressed the ability of transplanted BMDML cells to increase microglial TGF-β1R expression and decrease hippocampal Aβ levels. Taken together, these findings suggested that transplanted BMDML cells secreted TGF-β1 to stimulate Aβ phagocytosis by resident microglia and decrease brain Aβ pathology.