A novel role for osteopontin in macrophage-mediated amyloid-β clearance in Alzheimer's models

Osteopontin (OPN), a matricellular immunomodulatory cytokine highly expressed by myelomonocytic cells, is known to regulate immune cell migration, communication, and response to brain injury. Enhanced cerebral recruitment of monocytes achieved through glatiramer acetate (GA) immunization or peripheral blood enrichment with bone marrow (BM)-derived CD115(+) monocytes (Mo-Bm) curbs amyloid beta-protein (A beta) neuropathology and preserves cognitive function in murine models of Alzheimer's disease (ADtg mice). To elucidate the beneficial mechanisms of these immunomodulatory approaches in AD, we focused on the potential role of OPN in macrophage-mediated A beta clearance. Here, we found extensive OPN upregulation along with reduction of vascular and parenchymal A beta burden in cortices and hippocampi of GA-immunized ADtg mice. Treatment combining GA with blood-grafted Mo-Bm further increased OPN levels surrounding residual A beta plaques. In brains from AD patients and ADtg mice, OPN was also elevated and predominantly expressed by infiltrating GFr(+)- or Ibal(+)-CD45(high) monocytederived macrophages engulfing A beta plaques. Following GA immunization, we detected a significant increase in a subpopulation of inflammatory blood monocytes (CD115(+)CD11b(+)Ly6C(high)) expressing OPN, and subsequently, an elevated population of OPN-expressing CD11b(+)Ly6C(+)CD45(high) monocyte/ macrophages in the brains of these ADtg mice. Correlogram analyses indicate a strong linear correlation between cerebral OPN levels and macrophage infiltration, as well as a tight inverse relation between OPN and A beta-plaque burden. In vitro studies corroborate in vivo findings by showing that GA directly upregulates OPN expression in BM-derived macrophages (M Phi(Bm)). Further, OPN promotes a phenotypic shift that is highly phagocytic (increased uptake of A beta fibrils and surface scavenger receptors) and antiinflammatory (altered cell morphology, reduced iNOS, and elevated IL-10 and A beta-degrading enzyme MMP-9). Inhibition of OPN expression in M Phi(Bm), either by siRNA, knockout (KOOPN), or minocycline, impairs uptake of A beta fibrils and hinders GA's neuroprotective effects on macrophage immunological profile. Addition of human recombinant OPN reverses the impaired A beta phagocytosis in KOOPN-M Phi(BM). This study demonstrates that OPN has an essential role in modulating macrophage immunological profile and their ability to resist pathogenic forms of A beta. (C) 2017 The Author(s). Published by Elsevier Inc.