Neurotoxicity from innate immune response is greatest with targeted replacement of ε4 allele of apolipoprotein E gene and is mediated by microglial p38MAPK

Maezawa, Izumi; Nivison, Mary; Montine, Kathleen S.; Maeda, Nobuyo; Montine, Thomas J.

doi:10.1096/fj.05-5423fje

Cited by 98 publications

(139 citation statements)

References 63 publications

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“…Hippocampal slice cultures (400 μ m thick) were prepared from 7‐day‐old C57BL/6J mice as described 28. After 3 days , culture medium was changed to a hypoxic/hypoglycemic medium (75% Neurobasal, 25% HBSS, 1% L‐glutamine, bubbled with 99.4% nitrogen).…”

Section: Methodsmentioning

confidence: 99%

Inhibition of the potassium channel Kv1.3 reduces infarction and inflammation in ischemic stroke

Chen

Nguyen

Maezawa

et al. 2017

Ann Clin Transl Neurol

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ObjectiveInhibitors of the voltage‐gated K+ channel Kv1.3 are currently in development as immunomodulators for the treatment of autoimmune diseases. As Kv1.3 is also expressed on microglia and has been shown to be specifically up‐regulated on “M1‐like” microglia, we here tested the therapeutic hypothesis that the brain‐penetrant small‐molecule Kv1.3‐inhibitor PAP‐1 reduces secondary inflammatory damage after ischemia/reperfusion.MethodsWe studied microglial Kv1.3 expression using electrophysiology and immunohistochemistry, and evaluated PAP‐1 in hypoxia‐exposed organotypic hippocampal slices and in middle cerebral artery occlusion (MCAO) with 8 days of reperfusion in both adult male C57BL/6J mice (60 min MCAO) and adult male Wistar rats (90 min MCAO). In both models, PAP‐1 administration was started 12 h after reperfusion.ResultsWe observed Kv1.3 staining on activated microglia in ischemic infarcts in mice, rats, and humans and found higher Kv1.3 current densities in acutely isolated microglia from the infarcted hemisphere than in microglia isolated from the contralateral hemisphere of MCAO mice. PAP‐1 reduced microglia activation and increased neuronal survival in hypoxia‐exposed hippocampal slices as effectively as minocycline. In mouse MCAO, PAP‐1 dose‐dependently reduced infarct area, improved neurological deficit score, and reduced brain levels of IL‐1β and IFN‐γ without affecting IL‐10 and brain‐derived nerve growth factor (BDNF) levels or inhibiting ongoing phagocytosis. The beneficial effects on infarct area and neurological deficit score were reproduced in rats providing confirmation in a second species.InterpretationOur findings suggest that Kv1.3 constitutes a promising therapeutic target for preferentially inhibiting “M1‐like” inflammatory microglia/macrophage functions in ischemic stroke.

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Section: Methodsmentioning

confidence: 99%

Inhibition of the potassium channel Kv1.3 reduces infarction and inflammation in ischemic stroke

Chen

Nguyen

Maezawa

et al. 2017

Ann Clin Transl Neurol

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“…Primary Cultures-Primary microglia cultures derived from newborn C57BL/6J mice were prepared from mixed glia cultures (1-2 weeks in vitro) with the "shaking off" method as described previously (26). Cultures were Ն99% pure for microglia as demonstrated by anti-IBA1 immunostaining.…”

Section: Methodsmentioning

confidence: 99%

“…The neurons were cultured in NB/B27 at a density of 2.5 ϫ 10 5 cells/well in 12-well plates or 8 ϫ 10 5 cells/well in 6-well plates for at least 14 days before they were treated with microglia CM. Hippocampal slice cultures (400 m thick) were prepared from 7-day-old C57BL/6J mice as described previously (26) and cultured for 10 days in vitro before use. Neuronal damage in the slices was monitored by PI uptake following Bernardino et al (28).…”

Section: Methodsmentioning

confidence: 99%

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Amyloid-β Protein Oligomer at Low Nanomolar Concentrations Activates Microglia and Induces Microglial Neurotoxicity

Maezawa

Zimin²,

Wulff³

et al. 2011

Journal of Biological Chemistry

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247

218

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Neuroinflammation and associated neuronal dysfunction mediated by activated microglia play an important role in the pathogenesis of Alzheimer disease (AD). Microglia are activated by aggregated forms of amyloid-␤ protein (A␤), usually demonstrated in vitro by stimulating microglia with micromolar concentrations of fibrillar A␤, a major component of amyloid plaques in AD brains. Here we report that amyloid-␤ oligomer (A␤O), at 5-50 nM, induces a unique pattern of microglia activation that requires the activity of the scavenger receptor A and the Ca 2؉ -activated potassium channel KCa3.1. A␤O treatment induced an activated morphological and biochemical profile of microglia, including activation of p38 MAPK and nuclear factor B. Interestingly, although increasing nitric oxide (NO) production, A␤O did not increase several proinflammatory mediators commonly induced by lipopolyliposacharides or fibrillar A␤, suggesting that A␤O stimulates both common and divergent pathways of microglia activation. A␤O at low nanomolar concentrations, although not neurotoxic, induced indirect, microglia-mediated damage to neurons in dissociated cultures and in organotypic hippocampal slices. The indirect neurotoxicity was prevented by (i) doxycycline, an inhibitor of microglia activation; (ii) TRAM-34, a selective KCa3.1 blocker; and (iii) two inhibitors of inducible NO synthase, indicating that KCa3.1 activity and excessive NO release are required for A␤O-induced microglial neurotoxicity. Our results suggest that A␤O, generally considered a neurotoxin, may more potently cause neuronal damage indirectly by activating microglia in AD.A␤, 2 a hydrophobic protein derived from proteolytic processing of the amyloid-␤ precursor protein, self-aggregates into amyloid fibrils and deposits as amyloid plaques, one of the pathological hallmarks of AD. A␤ aggregates, especially those of the 42-residue A␤42, are potent toxins to neurons. In addition, A␤ aggregates activate microglia, which clear A␤, but in the process release inflammatory mediators that cause indirect neurotoxicity (1). A commonly held view is that microglia react to fA␤ deposited in amyloid plaques, which form a nidus for microglia-mediated neuronal damage. However, because the number of amyloid plaques correlates poorly with the degree of dementia (2, 3), it follows that plaque-associated microglia may not be a major player in cognitive impairment. Emerging evidence including two recent in vivo positron emission tomography studies indicates that microglia may respond to stimuli other than plaque fA␤ (4, 5), suggesting that alternative ways to activate microglia must occur in AD.In addition to fibrillar forms, A␤ exists in various smaller assemblies in AD brains, which may mediate diverse toxic effects at different stages of the disease. Although these smaller aggregates, variously named as oligomers (A␤O), protofibrils, amyloid pores, or AD diffusible ligands, have been considered transient or metastable intermediates in fibril formation (6), some of them may not be obligate inter...

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“…And the effect was gene dose-dependent and increased with the number of ApoE4 gene alleles. The higher production of cytoactive agents by ApoE4/4 microglia showed an increasing injury to neighboring cultured neurons [39] . In addition, LPS was injected into peritoneum of three different models ApoE3/3, ApoE3/0, and ApoE4/4 to detect the difference of the response among them [40] .…”

Section: The Variant Of Apoe Alleles and Inflammationmentioning

confidence: 97%

遗传基因的趋炎症性: 阿尔茨海默病的又一危险因素

2008

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Abstract:Inflammation has been shown to play an important role in the progression of Alzheimer's disease (AD). Recent epidemical study indicates that the incidence of AD in some populations is substantially influenced by the gene polymorphisms of the inflammation mediators. Meanwhile, an ensured risk factor, the ApoE ε4 allele is also reported to directly promote inflammation. Accordingly, it appears that an individual genetic background has partly determined his predisposition for AD by the extent of the inflammation response to the chronic stimulus by β-amyloid peptide (Aβ) deposits and other antigen stressor in the elderly. Hence we present a hypothesis that the inflammation genotypes may contribute to AD susceptibility. This may provide a new orientation both for future identification of individuals at risk and for personalized medication.

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Neurotoxicity from innate immune response is greatest with targeted replacement of ε4 allele of apolipoprotein E gene and is mediated by microglial p38MAPK

Cited by 98 publications

References 63 publications

Inhibition of the potassium channel Kv1.3 reduces infarction and inflammation in ischemic stroke

Inhibition of the potassium channel Kv1.3 reduces infarction and inflammation in ischemic stroke

Amyloid-β Protein Oligomer at Low Nanomolar Concentrations Activates Microglia and Induces Microglial Neurotoxicity

遗传基因的趋炎症性: 阿尔茨海默病的又一危险因素

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