Glia Maturation Factor‐Antibody Injection Reduces Behavioral Impairment, Neuro Inflammation and Amyloid Pathology in 5XFAD Mice Brains

Abstract Introduction Traumatic brain injury (TBI) is considered as the most robust environmental risk factor for Alzheimer’s disease (AD). Besides direct neuronal injury and neuroinflammation, vascular impairment is also a hallmark event of the pathological cascade after TBI. However, the vascular connection between TBI and subsequent AD pathogenesis remains underexplored. Methods In a closed-head mild TBI (mTBI) model in mice with controlled cortical impact, we examined the time courses of microvascular injury, blood–brain barrier (BBB) dysfunction, gliosis and motor function impairment in wild type C57BL/6 mice. We also evaluated the BBB integrity, amyloid pathology as well as cognitive functions after mTBI in the 5xFAD mouse model of AD. Results mTBI induced microvascular injury with BBB breakdown, pericyte loss, basement membrane alteration and cerebral blood flow reduction in mice, in which BBB breakdown preceded gliosis. More importantly, mTBI accelerated BBB leakage, amyloid pathology and cognitive impairment in the 5xFAD mice. Discussion Our data demonstrated that microvascular injury plays a key role in the pathogenesis of AD after mTBI. Therefore, restoring vascular functions might be beneficial for patients with mTBI, and potentially reduce the risk of developing AD.

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Dual effect of glia maturation factor on astrocytes

Journal of Neuroimmunology ◽

10.1016/0165-5728(83)90046-2 ◽

1983 ◽

Vol 5 (3) ◽

pp. 261-269 ◽

Cited By ~ 16

Author(s):

A. Fontana ◽

E. Weber ◽

P.J. Grob ◽

R. Lim ◽

J.F. Miller

Keyword(s):

Glia Maturation Factor ◽

Dual Effect ◽

Maturation Factor

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Glia maturation factor-γ regulates murine macrophage iron metabolism and M2 polarization through mitochondrial ROS

Blood Advances ◽

10.1182/bloodadvances.2018026070 ◽

2019 ◽

Vol 3 (8) ◽

pp. 1211-1225 ◽

Cited By ~ 2

Author(s):

Wulin Aerbajinai ◽

Manik C. Ghosh ◽

Jie Liu ◽

Chutima Kumkhaek ◽

Jianqing Zhu ◽

...

Keyword(s):

Iron Metabolism ◽

Mitochondrial Function ◽

Regulatory Protein ◽

M2 Macrophage ◽

Macrophage Phenotype ◽

Glia Maturation Factor ◽

Altered Expression ◽

Murine Macrophages ◽

Cellular Iron ◽

Maturation Factor

Abstract In macrophages, cellular iron metabolism status is tightly integrated with macrophage phenotype and associated with mitochondrial function. However, how molecular events regulate mitochondrial activity to integrate regulation of iron metabolism and macrophage phenotype remains unclear. Here, we explored the important role of the actin-regulatory protein glia maturation factor-γ (GMFG) in the regulation of cellular iron metabolism and macrophage phenotype. We found that GMFG was downregulated in murine macrophages by exposure to iron and hydrogen peroxide. GMFG knockdown altered the expression of iron metabolism proteins and increased iron levels in murine macrophages and concomitantly promoted their polarization toward an anti-inflammatory M2 phenotype. GMFG-knockdown macrophages exhibited moderately increased levels of mitochondrial reactive oxygen species (mtROS), which were accompanied by decreased expression of some mitochondrial respiration chain components, including the iron-sulfur cluster assembly scaffold protein ISCU as well as the antioxidant enzymes SOD1 and SOD2. Importantly, treatment of GMFG-knockdown macrophages with the antioxidant N-acetylcysteine reversed the altered expression of iron metabolism proteins and significantly inhibited the enhanced gene expression of M2 macrophage markers, suggesting that mtROS is mechanistically linked to cellular iron metabolism and macrophage phenotype. Finally, GMFG interacted with the mitochondrial membrane ATPase ATAD3A, suggesting that GMFG knockdown–induced mtROS production might be attributed to alteration of mitochondrial function in macrophages. Our findings suggest that GMFG is an important regulator in cellular iron metabolism and macrophage phenotype and could be a novel therapeutic target for modulating macrophage function in immune and metabolic disorders.

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Antiproliferative function of glia maturation factor beta.

Cell Regulation ◽

10.1091/mbc.1.10.741 ◽

1990 ◽

Vol 1 (10) ◽

pp. 741-746 ◽

Cited By ~ 14

Author(s):

R Lim ◽

W X Zhong ◽

A Zaheer

Keyword(s):

Growth Factors ◽

Growth Factor ◽

Target Cell ◽

G1 Phase ◽

Glia Maturation Factor ◽

Pituitary Extract ◽

Mitogenic Effect ◽

Maturation Factor ◽

Cultured Astrocytes

Recombinant human glia maturation factor beta (GMF-beta) reversibly inhibits the proliferation of neoplastic cells in culture by arresting the cells in the G0/G1 phase. This phenomenon is not target-cell specific, as neural and nonneural cells are equally inhibited. When tested simultaneously, GMF-beta suppresses the mitogenic effect of acidic fibroblasts growth factor (aFGF), but the two are synergistic in promoting the morphologic differentiation of cultured astrocytes. GMF-beta also counteracts the growth-stimulating effect of pituitary extract and cholera toxin on Schwann cells. The results underscore the regulatory role of GMF-beta and its intricate interaction with the mitogenic growth factors.

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