ABSTRACT
Accumulation of amyloid-ß (Aß) 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 Aß phagocytosis. High levels of transforming growth factor-ß1 (TGF-ß1) were present in the conditioned medium, and BMDML cells and microglia expressed Tgf-ß1 mRNA and TGF-ß receptor type 1 (TGF-ßR1) protein, respectively. BMDML conditioned medium also induced microglial Smad2/3 phosphorylation. A TGF-ßR1 inhibitor suppressed Smad2/3 phosphorylation and promotion of microglial Aß phagocytosis induced by conditioned medium. Recombinant mouse TGF-ß1 similarly increased microglial Aß phagocytosis and induced Smad2/3 phosphorylation, which were suppressed by the TGF-ßR1 inhibitor. Brain TGF-ß1 levels and resident microglial TGF-ß1R expression were increased by intrahippocampal injection of BMDML cells in a mouse model of AD. Cotreatment with the TGF-ßR1 inhibitor suppressed the ability of transplanted BMDML cells to increase microglial TGF-ß1R expression and decrease hippocampal Aß levels. Taken together, these findings suggested that transplanted BMDML cells secreted TGF-ß1 to stimulate Aß phagocytosis by resident microglia and decrease brain Aß pathology.
