Signal Regulatory Protein-β1 A Microglial Modulator of Phagocytosis in Alzheimer's Disease

The signal regulatory protein-beta 1 (SIRP beta 1) is a DAP12-associated transmembrane receptor expressed in a subset of hematopoietic cells. Recently, it was shown that peritoneal macrophages express SIRP beta 1, which positively regulated phagocytosis. Here, we found that SIRP beta 1 was up-regulated and acted as a phagocytic receptor on microglia in amyloid precursor protein J20 (APP/J20) transgenic mice and in Alzheimer's disease (AD) patients. Interferon (IEFN)-gamma and IFN-beta stimulated gene transcription of SIRP beta 1 in cultured microglia. Activation of SIRP beta 1 on cultured microglia by cross-linking antibodies induced reorganization of the cytoskeleton protein beta-actin and suppressed lipopolysaccharide-induced gene transcription of tumor necrosis factor-alpha and nitric oxide synthase-2. Furthermore, activation of SIRP beta 1 increased phagocytosis of microsphere beads, neural debris, and fibrillary amyloid-beta (A beta). Phagocytosis; of neural cell debris and A beta was impaired after lentiviral knockdown of SIRP beta 1 in primary microglial cells. Thus, SIRP beta 1 is a novel EFN-induced microglial receptor that supports clearance of neural debris and A beta aggregates by stimulating phagocytosis. (Am J Pathol 2009, 175:2528-2539; DOI: 10.2353/ajpath.2009.090147)