Genome-wide transcriptomic analysis of microglia reveals impaired responses in aged mice after cerebral ischemia

Shi, Ligen; Rocha, Marcelo; Zhang, Wenting; Jiang, Ming; Li, Sicheng; Ye, Qing; Hassan, Sulaiman H; Liu, Liqiang; Adair, Maya N; Xu, Jing; Luo, Jianhua; Hu, Xiaoming; Wechsler, Lawrence R.; Chen, Jun; Shi, Yejie

doi:10.1177/0271678x20925655

Cited by 50 publications

(45 citation statements)

References 78 publications

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“…[57][58][59] Transcriptomic analysis also suggests impaired microglia response to cerebral ischemia in aged mice compared with young mice. 60 In the current study, since there is a dramatic change in phenotype after NAMPT deletion, 17 the effect of NAMPT deletion on metabolism and other pathways should supersede other factors including age and sex, and thus the relative effect of NAMPT deletion is likely the same between male and female, and young and aged mice.…”

Section: Discussionmentioning

confidence: 82%

Metabolomic and transcriptional profiling reveals bioenergetic stress and activation of cell death and inflammatory pathways in vivo after neuronal deletion of NAMPT

Lundt

Zhang

et al. 2021

J Cereb Blood Flow Metab

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Nicotinamide phosphoribosyltransferase (NAMPT) is the rate-limiting enzyme in the NAD+ salvage pathway. Our previous study demonstrated that deletion of NAMPT gene in projection neurons using Thy1-NAMPT−/− conditional knockout (cKO) mice causes neuronal degeneration, muscle atrophy, neuromuscular junction abnormalities, paralysis and eventually death. Here we conducted a combined metabolomic and transcriptional profiling study in vivo in an attempt to further investigate the mechanism of neuronal degeneration at metabolite and mRNA levels after NAMPT deletion. Here using steady-state metabolomics, we demonstrate that deletion of NAMPT causes a significant decrease of NAD+ metabolome and bioenergetics, a buildup of metabolic intermediates upstream of glyceraldehyde 3-phosphate dehydrogenase (GAPDH) in glycolysis, and an increase of oxidative stress. RNA-seq shows that NAMPT deletion leads to the increase of mRNA levels of enzymes in NAD metabolism, in particular PARP family of NAD+ consumption enzymes, as well as glycolytic genes Glut1, Hk2 and PFBFK3 before GAPDH. GO, KEGG and GSEA analyses show the activations of apoptosis, inflammation and immune responsive pathways and the inhibition of neuronal/synaptic function in the cKO mice. The current study suggests that increased oxidative stress, apoptosis and neuroinflammation contribute to neurodegeneration and mouse death as a direct consequence of bioenergetic stress after NAMPT deletion.

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Section: Discussionmentioning

confidence: 82%

Metabolomic and transcriptional profiling reveals bioenergetic stress and activation of cell death and inflammatory pathways in vivo after neuronal deletion of NAMPT

Lundt

Zhang

et al. 2021

J Cereb Blood Flow Metab

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“…This enzyme has been suggested to be enriched in AD pathology progression [ 144 ] and increased in the hippocampus of AD brains [ 64 ]. CLEC7A (FC = 2.02, p = 0.02) is a disease-associated microglia gene which has been shown to increase after TBI in mice [ 19 ], in a mouse model of AD [ 38 , 56 ], and in aged microglia associated with neurodegenerative disease [ 135 ]. DAPK1 (FC = 1.08, p = 0.05) is a calcium-dependent serine/threonine kinase that is highly expressed in the cortex in AD [ 167 ], after ischemic damage [ 154 ], and in physiological ageing where it has been suggested to play a role in the decay of learning and memory with age [ 51 ].…”

Section: Resultsmentioning

confidence: 99%

Early onset senescence and cognitive impairment in a murine model of repeated mTBI

Schwab

Hazrati

2021

acta neuropathol commun

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Mild traumatic brain injury (mTBI) results in broad neurological symptoms and an increased risk of being diagnosed with a neurodegenerative disease later in life. While the immediate oxidative stress response and post-mortem pathology of the injured brain has been well studied, it remains unclear how early pathogenic changes may drive persistent symptoms and confer susceptibility to neurodegeneration. In this study we have used a mouse model of repeated mTBI (rmTBI) to identify early gene expression changes at 24 h or 7 days post-injury (7 dpi). At 24 h post-injury, gene expression of rmTBI mice shows activation of the DNA damage response (DDR) towards double strand DNA breaks, altered calcium and cell–cell signalling, and inhibition of cell death pathways. By 7 dpi, rmTBI mice had a gene expression signature consistent with induction of cellular senescence, activation of neurodegenerative processes, and inhibition of the DDR. At both timepoints gliosis, microgliosis, and axonal damage were evident in the absence of any gross lesion, and by 7 dpi rmTBI also mice had elevated levels of IL1β, p21, 53BP1, DNA2, and p53, supportive of DNA damage-induced cellular senescence. These gene expression changes reflect establishment of processes usually linked to brain aging and suggests that cellular senescence occurs early and most likely prior to the accumulation of toxic proteins. These molecular changes were accompanied by spatial learning and memory deficits in the Morris water maze. To conclude, we have identified DNA damage-induced cellular senescence as a repercussion of repeated mild traumatic brain injury which correlates with cognitive impairment. Pathways involved in senescence may represent viable treatment targets of post-concussive syndrome. Senescence has been proposed to promote neurodegeneration and appears as an effective target to prevent long-term complications of mTBI, such as chronic traumatic encephalopathy and other related neurodegenerative pathologies.

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“…55 Moreover, microglia/macrophages appear to be heterogeneous with diverse functional phenotypes that range from immuno-enhanced phenotypes to anti-inflammatory phenotypes. 56 Considering the unique roles of microglia/macrophages, the promotion of neurogenesis and angiogenesis produced by the activation of the immune-suppressive microglia phenotype may play a vital part in stimulating neuroprotective mechanisms to protect neurons from injury. 12,16,47,57 However, whether these complex phenotypes of microglia/macrophages could be directly or indirectly affected by SPC, and whether this polarization of phenotypes was influenced by sex or sex related signaling, still needs to be studied in the future.…”

Section: Limitationsmentioning

confidence: 99%

Sevoflurane preconditioning protects experimental ischemic stroke by enhancing anti‐inflammatory microglia/macrophages phenotype polarization through GSK‐3β/Nrf2 pathway

et al. 2021

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Genome-wide transcriptomic analysis of microglia reveals impaired responses in aged mice after cerebral ischemia

Cited by 50 publications

References 78 publications

Metabolomic and transcriptional profiling reveals bioenergetic stress and activation of cell death and inflammatory pathways in vivo after neuronal deletion of NAMPT

Metabolomic and transcriptional profiling reveals bioenergetic stress and activation of cell death and inflammatory pathways in vivo after neuronal deletion of NAMPT

Early onset senescence and cognitive impairment in a murine model of repeated mTBI

Sevoflurane preconditioning protects experimental ischemic stroke by enhancing anti‐inflammatory microglia/macrophages phenotype polarization through GSK‐3β/Nrf2 pathway

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