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See detailPhagocytosis‐related NADPH oxidase 2 subunit gp91phox contributes to neurodegeneration after repeated systemic challenge with lipopolysaccharides
Shahraz, Anahita; Wißfeld, Jannis; Ginolhac, Aurélien UL et al

in Glia (2020)

Repeated systemic challenge with lipopolysaccharides (LPS) can induce microglia activation and inflammatory neurodegeneration in the substantia nigra pars compacta region of mice. We now explored the role ... [more ▼]

Repeated systemic challenge with lipopolysaccharides (LPS) can induce microglia activation and inflammatory neurodegeneration in the substantia nigra pars compacta region of mice. We now explored the role of mononuclear phagocytes associated nicotinamide adenine dinucleotide phosphate oxidase 2 (NOX‐2) in inflammatory neurodegeneration. Cybb ‐deficient NOX‐2 knock‐out (KO) and control wild type (WT) mice were treated intraperitoneally daily over four consecutive days with 1 μg/gbw/day LPS. Transcriptome analysis by RNA‐seq of total brain tissue indicated increased LPS‐induced upregulation of genes belonging to the reactive oxygen species and reactive nitrogen species production, complement and lysosome activation as well as apoptosis and necroptosis in WT compared to NOX‐2 KO mice. Validation of up‐regulated gene transcripts via qRT‐PCR confirmed that LPS‐challenged NOX‐2 KO mice expressed lower levels of the microglial phagocytosis‐related genes Nos2 , Cd68 , Aif1/Iba1 , Cyba , Itgam , and Fcer1g compared to WT mice at Day 5 after systemic inflammatory challenge, but no significant differences in the pro‐inflammatory genes Tnfα and Il1b as well as microglial IBA1 and CD68 intensities were observed between both genotypes. Furthermore, loss of tyrosine hydroxylase positive (TH+) and NeuN positive neurons in the substantia nigra pars compacta upon repeated systemic LPS application were attenuated in NOX‐2 KO mice. Thus, our data demonstrate that loss of dopaminergic neurons in the substantia nigra pars compacta after repeated systemic challenge with LPS is associated with a microglial phagocytosis‐related gene activation profile involving the NADPH oxidase subunit Cybb/gp91phox. [less ▲]

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See detailReduced sialylation triggers homeostatic synapse and neuronal loss in middle-aged mice
Klaus, Christine; Hansen, Jan N.; Ginolhac, Aurélien UL et al

in Neurobiology of Aging (2020)

Sialic acid-binding receptors (Siglecs) are linked to neurodegenerative processes, but the role of sialic acids in physiological aging is still not fully understood. We investigated the impact of reduced ... [more ▼]

Sialic acid-binding receptors (Siglecs) are linked to neurodegenerative processes, but the role of sialic acids in physiological aging is still not fully understood. We investigated the impact of reduced sialylation in the brain of mice heterozygous for the enzyme glucosamine-2-epimerase/N-acetylmannosamine kinase (GNE+/-) that is essential for sialic acid biosynthesis. We demonstrate that GNE+/- mice have hyposialylation in different brain regions, less synapses in the hippocampus and reduced microglial arborization already at 6 months followed by increased loss of neurons at 12 months. A transcriptomic analysis revealed no pro-inflammatory changes indicating an innate homeostatic immune process leading to the removal of synapses and neurons in GNE+/- mice during aging. Crossbreeding with complement C3-deficient mice rescued the earlier onset of neuronal and synaptic loss as well as the changes in microglial arborization. Thus, sialic acids of the glycocalyx contribute to brain homeostasis and act as a recognition system for the innate immune system in the brain. [less ▲]

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See detailTREM2 triggers microglial density and age‐related neuronal loss
Linnartz-Gerlach, Bettina; Bodea, Liviu-Gabriel; Klaus, Christine et al

in Glia (2018)

The microglial triggering receptor expressed on myeloid cells 2 (TREM2) signals via the activatory membrane adaptor molecule TYROBP. Genetic variants or mutations of TREM2 or TYROBP have been linked to ... [more ▼]

The microglial triggering receptor expressed on myeloid cells 2 (TREM2) signals via the activatory membrane adaptor molecule TYROBP. Genetic variants or mutations of TREM2 or TYROBP have been linked to inflammatory neurodegenerative diseases associated with aging. The typical aging process goes along with microglial changes and mild neuronal loss, but the exact contribution of TREM2 is still unclear. Aged TREM2 knock‐out mice showed decreased age‐related neuronal loss in the substantia nigra and the hippocampus. Transcriptomic analysis of the brains of 24 months old TREM2 knock‐out mice revealed 211 differentially expressed genes mostly downregulated and associated with complement activation and oxidative stress response pathways. Consistently, 24 months old TREM2 knock‐out mice showed lower transcription of microglial (Aif1 and Tmem119), oxidative stress markers (Inos, Cyba, and Cybb) and complement components (C1qa, C1qb, C1qc, C3, C4b, Itgam, and Itgb2), decreased microglial numbers and expression of the microglial activation marker Cd68, as well as accumulation of oxidized lipids. Cultured microglia of TREM2 knock‐out mice showed reduced phagocytosis and oxidative burst. Thus, microglial TREM2 contributes to age‐related microglial changes, phagocytic oxidative burst, and loss of neurons with possible detrimental effects during physiological aging. [less ▲]

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See detailNeurodegeneration by Activation of the Microglial Complement–Phagosome Pathway
Bodea, Liviu-Gabriel; Wang, Yiner; Linnartz-Gerlach, Bettina et al

in Journal of Neuroscience (2014), 34(25), 8546-8556

Systemic inflammatory reactions have been postulated to exacerbate neurodegenerative diseases via microglial activation. We now demonstrate in vivo that repeated systemic challenge of mice over four ... [more ▼]

Systemic inflammatory reactions have been postulated to exacerbate neurodegenerative diseases via microglial activation. We now demonstrate in vivo that repeated systemic challenge of mice over four consecutive days with bacterial LPS maintained an elevated microglial inflammatory phenotype and induced loss of dopaminergic neurons in the substantia nigra. The same total cumulative LPS dose given within a single application did not induce neurodegeneration. Whole-genome transcriptome analysis of the brain demonstrated that repeated systemic LPS application induced an activation pattern involving the classical complement system and its associated phagosome pathway. Loss of dopaminergic neurons induced by repeated systemic LPS application was rescued in complement C3-deficient mice, confirming the involvement of the complement system in neurodegeneration. Our data demonstrate that a phagosomal inflammatory response of microglia is leading to complement-mediated loss of dopaminergic neurons. [less ▲]

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