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Nox2 dependent redox-regulation of microglial response to amyloid-? stimulation and microgliosis in aging.

ABSTRACT: Microglia express constitutively a Nox2 enzyme that is involved in neuroinflammation by the generation of reactive oxygen species (ROS). Amyloid ? (A?) plays a crucial role in Alzheimer's disease. However, the mechanism of A?-induced microglial dysfunction and redox-regulation of microgliosis in aging remains unclear. In this study, we examined Nox2-derived ROS in mediating microglial response to A? peptide 1-42 (A?42) stimulation in vitro, in aging-associated microgliosis in vivo and in post-mortem human samples. Compared to controls, A?42 markedly induced BV2 cell ROS production, Nox2 expression, p47phox and ERK1/2 phosphorylation, cell proliferation and IL-1? secretion. All these changes could be inhibited to the control levels in the presence of Nox2 inhibitor or superoxide scavenger. Compared to young (3-4 months) controls, midbrain tissues from wild-type aging mice (20-22 months) had significantly higher levels of Nox2-derived ROS production, A? deposition, microgliosis and IL-1? production. However, these aging-related changes were reduced or absent in Nox2 knockout aging mice. Clinical significance of aging-associated Nox2 activation, microgliosis and IL-1? production was investigated using post-mortem midbrain tissues of humans at young (25-38 years) and old age (61-85 years). In conclusion, Nox2-dependent redox-signalling is crucial in microglial response to A?42 stimulation and in aging-associated microgliosis and brain inflammation.

SUBMITTER: Geng L

PROVIDER: S-EPMC6994719 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Nox2 dependent redox-regulation of microglial response to amyloid-β stimulation and microgliosis in aging.

Geng Li L Fan Lampson M LM Liu Fangfei F Smith Colin C Li Jian -Mei J-

Scientific reports 20200131 1

Microglia express constitutively a Nox2 enzyme that is involved in neuroinflammation by the generation of reactive oxygen species (ROS). Amyloid β (Aβ) plays a crucial role in Alzheimer's disease. However, the mechanism of Aβ-induced microglial dysfunction and redox-regulation of microgliosis in aging remains unclear. In this study, we examined Nox2-derived ROS in mediating microglial response to Aβ peptide 1-42 (Aβ<sub>42</sub>) stimulation in vitro, in aging-associated microgliosis in vivo and ...[more]

PMID: 32005915

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Project description:Alzheimer's disease (AD) is characterized by a progressive cognitive decline and believed to be driven by the self-aggregation of amyloid-? (A?) peptide into oligomers and fibrils that accumulate as senile plaques. It is widely accepted that microglia-mediated inflammation is a significant contributor to disease pathogenesis; however, different microglia phenotypes were identified along AD progression and excessive A? production was shown to dysregulate cell function. As so, the contribution of microglia to AD pathogenesis remains to be elucidated. In this study, we wondered if isolated microglia cultured for 16 days in vitro (DIV) would react differentially from the 2 DIV cells upon treatment with 1000 nM A?1-42 for 24 h. No changes in cell viability were observed and morphometric alterations associated to microglia activation, such as volume increase and process shortening, were obvious in 2 DIV microglia, but less evident in 16 DIV cells. These cells showed lower phagocytic, migration and autophagic properties after A? treatment than the 2 DIV cultured microglia. Reduced phagocytosis may derive from increased CD33 expression, reduced triggering receptor expressed on myeloid cells 2 (TREM2) and milk fat globule-EGF factor 8 protein (MFG-E8) levels, which were mainly observed in 16 DIV cells. Activation of inflammatory mediators, such as high mobility group box 1 (HMGB1) and pro-inflammatory cytokines, as well as increased expression of Toll-like receptor 2 (TLR2), TLR4 and fractalkine/CX3C chemokine receptor 1 (CX3CR1) cell surface receptors were prominent in 2 DIV microglia, while elevation of matrix metalloproteinase 9 (MMP9) was marked in 16 DIV cells. Increased senescence-associated ?-galactosidase (SA-?-gal) and upregulated miR-146a expression that were observed in 16 DIV cells showed to increase by A? in 2 DIV microglia. Additionally, A? downregulated miR-155 and miR-124, and reduced the CD11b+ subpopulation in 2 DIV microglia, while increased the number of CD86+ cells in 16 DIV microglia. Simultaneous M1 and M2 markers were found after A? treatment, but at lower expression in the in vitro aged microglia. Data show key-aging associated responses by microglia when incubated with A?, with a loss of reactivity from the 2 DIV to the 16 DIV cells, which course with a reduced phagocytosis, migration and lower expression of inflammatory miRNAs. These findings help to improve our understanding on the heterogeneous responses that microglia can have along the progression of AD disease and imply that therapeutic approaches may differ from early to late stages.

Dataset Information

Nox2 dependent redox-regulation of microglial response to amyloid-? stimulation and microgliosis in aging.

Publications

Nox2 dependent redox-regulation of microglial response to amyloid-β stimulation and microgliosis in aging.

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