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Quantitative 3D In Silico Modeling q3DISM of Cerebral Amyloid-beta Phagocytosis in Rodent Models of Alzheimer's Disease
Published on: December 26, 2016
Glia maturation factor-γ regulates amyloid-β42 phagocytosis through scavenger receptor class A type I in murine
Wulin Aerbajinai1, Jianqiong Zhu1, Kyung Chin1
1Molecular and Clinical Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, BG 10, RM 9N113, 10 Center Dr., Bethesda, MD 20892, United States.
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.
Insights
Glia maturation factor-gamma (GMFG) regulates macrophage clearance of amyloid-beta (Aβ) by controlling scavenger receptor expression. Reducing GMFG enhances Aβ uptake, offering potential Alzheimer
Area of Science:
- Neuroscience
- Immunology
- Cell Biology
Background:
- Dysfunctional amyloid-beta (Aβ) clearance by immune cells is linked to Alzheimer's disease (AD).
- The precise mechanisms behind impaired Aβ phagocytosis in macrophages remain unclear.
- Glia maturation factor-gamma (GMFG), an actin-disassembly protein, is highly expressed in immune cells.
Purpose of the Study:
- To investigate the role of GMFG in macrophage phagocytosis of Aβ.
- To determine GMFG's influence on type I class A scavenger receptor expression and function.
- To elucidate the molecular pathways involving GMFG in Aβ clearance.
Main Methods:
- GMFG knockdown and overexpression in bone marrow-derived macrophages and RAW264.7 cells.
- Assessment of Aβ42 uptake via phagocytosis assays.
- Analysis of type I class A scavenger receptor expression, ubiquitination, and phosphorylation.
- Investigation of downstream signaling pathways including MafB and RanBP2 interactions.
Main Results:
- GMFG knockdown significantly increased macrophage Aβ42 phagocytosis, while overexpression reduced it.
- GMFG knockdown enhanced type I class A scavenger receptor expression and Aβ uptake, confirmed by antibody blocking.
- GMFG modulated Aβ42-induced ubiquitination and phosphorylation of the scavenger receptor, involving MafB and RanBP2.
Conclusions:
- GMFG acts as a novel negative regulator of type I class A scavenger receptor-mediated Aβ phagocytosis in macrophages.
- Understanding GMFG's role provides insights into potential therapeutic strategies for Alzheimer's disease.
- Targeting GMFG may enhance immune cell clearance of Aβ, potentially slowing AD progression.
