Glia maturation factor-γ regulates amyloid-β42 phagocytosis through scavenger receptor class A type I in murine macrophages.

Abstract

Dysfunctional phagocytic clearance of β-amyloid (Aβ) in microglia and peripheral macrophages/monocytes has been implicated in Alzheimer's disease, but the mechanisms underlying this dysfunction are not yet well understood. In this study, we examined the role of glia maturation factor-γ (GMFG), an actin-disassembly protein, i.e. highly expressed in immune cells, in macrophage Aβ phagocytosis and in regulating type I class A scavenger receptor, a cell-surface receptor that has previously been implicated in Aβ clearance. GMFG knockdown-increased phagocytosis of Aβ42 in bone marrow-derived macrophages and RAW264.7 murine macrophages, while GMFG overexpression reduced Aβ42 uptake in these cells. Blocking with anti-type I class A scavenger receptor antibodies inhibited Aβ42 uptake in GMFG-knockdown cells, establishing a role for type I class A scavenger receptor in Aβ42 phagocytosis. GMFG knockdown-increased type I class A scavenger receptor protein expression under both basal conditions and in response to Aβ42 treatment via both the transcriptional and posttranscriptional levels in RAW264.7 macrophages. GMFG knockdown modulated Aβ42-induced K48-linked and K63-polyubiquitination of type I class A scavenger receptor, the phosphorylation of type I class A scavenger receptor and c-Jun N-Terminal kinase (JNK), suggesting that GMFG plays a role for intracellular signaling in the type I class A scavenger receptor--mediated uptake of Aβ. Further, GMFG-knockdown cells displayed increased levels of the transcriptional factor MafB, and silencing of MafB in these cells reduced their type I class A scavenger receptor expression. Finally, GMFG was found to interact with the nuclear pore complex component RanBP2, and silencing of RanBP2 in GMFG-knockdown cells reduced their type I class A scavenger receptor expression. Collectively, these data support the role of GMFG as a novel regulator of type I class A scavenger receptor in macrophage Aβ phagocytosis and may provide insight into therapeutic approaches to potentially slow or prevent the progression of Alzheimer's disease.