Nogo receptor impairs the clearance of fibril amyloid‐β by microglia and accelerates Alzheimer’s‐like disease progression

Wang, Jianbo; Qin, Xiaoying; Sun, Hao; He, Meijun; Lv, Qunyu; Gao, Congcong; He, Xinran; Liao, Hong

doi:10.1111/acel.13515

Cited by 20 publications

(7 citation statements)

References 53 publications

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“…When the brain is subjected to various stimuli such as pathogens, the microglia execute defense functions, including synapse remodeling and removal of cellular debris, in response to these changes, thereby maintaining brain homeostasis [ 10 ]. Once the Aβ plaques outside neurons are recognized by the microglia, on the one hand, they are activated to release pro-inflammatory factors leading to neuroinflammation [ 11 ], and on the other, they migrate and gather around the plaques to engulf them [ 12 ]. Disruption of this balance between neuroinflammation and phagocytosis accelerates the progression of AD [ 13 ].…”

Section: Introductionmentioning

confidence: 99%

The Neuroprotection of Verbascoside in Alzheimer’s Disease Mediated through Mitigation of Neuroinflammation via Blocking NF-κB-p65 Signaling

et al. 2022

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Verbascoside (VB) is a phenylethanoid glycoside extracted from the herbaceous plant Verbascum sinuatum and plays a neuroprotective role in Alzheimer’s disease (AD). The goal of this study was to explore the neuroprotective mechanism of VB. Based on the proteomics analysis, immunohistochemistry, immunofluorescence, Western blot, and ELISA were utilized to explore the neuroprotective mechanism of VB in context of neuroinflammation in APP/PS1 mice, LPS-induced BV2 cells, and/or Aβ1-42-stimulated N2a cells. Proteomic analysis demonstrated that the neuroprotection of VB correlated closely to its anti-inflammatory effect. VB significantly blocked microglia and astrocyte against activation in brains of APP/PS1 mice, suppressed the generation of IL-1β as well as IL-6, and boosted that of IL-4, IL-10 and TGF-β in vivo, which were analogous to results acquired in vitro. Furthermore, VB effectively restrained the phosphorylation of IKKα+β, IκBα, and NF-κB-p65 in APP/PS1 mice; LPS-induced BV2 cells, and Aβ1-42-stimulated N2a cells and lowered the tendency of NF-κB-p65 translocation towards nucleus in vitro. These results demonstrate that the neuroprotective effect of VB correlates to the modulation of neuroinflammation via NF-κB-p65 pathway, making VB as a hopeful candidate drug for the prevention and treatment of AD.

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Section: Introductionmentioning

confidence: 99%

The Neuroprotection of Verbascoside in Alzheimer’s Disease Mediated through Mitigation of Neuroinflammation via Blocking NF-κB-p65 Signaling

et al. 2022

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“…Phagocytosis, one of the most important feature of microglia, has been reported to be decreased significantly in AD mice [ 3 , 40 – 42 ]. Moreover, recent studies showed that the phagocytic activity of mouse primary microglial cells was markedly decreased with A β stimulation, which is associated with mitochondrial dysfunction concluding reduction of OCR [ 3 , 42 ].…”

Section: Resultsmentioning

confidence: 99%

Alzheimer’s Amyloid-β Accelerates Cell Senescence and Suppresses the SIRT1/NRF2 Pathway in Human Microglial Cells

et al. 2022

Oxidative Medicine and Cellular Longevity

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Microglia play important roles in maintenance of brain homeostasis, while due to some pathological stimuli in aging-related neurodegenerative diseases including Alzheimer’s disease, they are malfunctioning. Here, we demonstrated that amyloid-β (Aβ) accelerated cell senescence characterized by the upregulation of p21 and PAI-1 as well as senescence-associated beta-galactosidase (SA-β-gal) in human microglial cells. Consistently, Aβ induced the senescence-associated mitochondrial dysfunctions such as repression of ATP production, oxygen consumption rate (OCR), and mitochondrial membrane potential and enhancement of ROS production. Furthermore, Aβ was found to significantly suppress mRNA expression and protein level of Sirtuin-1 (SIRT1), a key regulator of senescence, and inhibit mRNA expression and translocation of NRF2, a critical transcription factor in inflammatory responses, leading to impairment of phagocytosis. Rescue of SIRT1, as expected, could counteract the pathological effects of Aβ. In summary, our findings revealed that Aβ accelerates human microglial senescence mainly through its suppression of the SIRT1/NRF2 pathway and suggested that genetic and pharmaceutical rescue of SIRT1 may provide a potential alternative treatment.

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“…In our study, we applied rAAV6 capsid variants with triple Y731F/Y705F/T492V mutation, which facilitated microglia infection in vivo and in vitro [ 25 ]. This construct and its based Cre-DIO system have been recently verified in microglia by several animal studies [ 26 , 27 ]. Besides, peripheral infiltrated cells were scarce in the intact mouse brain.…”

Section: Discussionmentioning

confidence: 99%

CD11c+ microglia promote white matter repair after ischemic stroke

Jia

Zheng

et al. 2023

Cell Death Dis

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Ischemic stroke leads to white matter damage and neurological deficits. However, the characteristics of white matter injury and repair after stroke are unclear. Additionally, the precise molecular communications between microglia and white matter repair during the stroke rehabilitation phase remain elusive. In this current study, MRI DTI scan and immunofluorescence staining were performed to trace white matter and microglia in the mouse transient middle cerebral artery occlusion (tMCAO) stroke model. We found that the most serious white matter damage was on Day 7 after the ischemic stroke, then it recovered gradually from Day 7 to Day 30. Parallel to white matter recovery, we observed that microglia centered around the damaged myelin sheath and swallowed myelin debris in the ischemic areas. Then, microglia of the ischemic hemisphere were sorted by flow cytometry for RNA sequencing and subpopulation analysis. We found that CD11c+ microglia increased from Day 7 to Day 30, demonstrating high phagocytotic capabilities, myelin-supportive genes, and lipid metabolism associated genes. CD11c+ microglia population was partly depleted by the stereotactic injecting of rAAV2/6M-taCasp3 (rAAV2/6M-CMV-DIO-taCasp3-TEVp) into CD11c-cre mice. Selective depletion of CD11c+ microglia disrupted white matter repair, oligodendrocyte maturation, and functional recovery after stroke by Rotarod test, Adhesive Removal test, and Morris Water Maze test. These findings suggest that spontaneous white matter repair occurs after ischemic stroke, while CD11c+ microglia play critical roles in this white matter restorative progress.

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Nogo receptor impairs the clearance of fibril amyloid‐β by microglia and accelerates Alzheimer’s‐like disease progression

Cited by 20 publications

References 53 publications

The Neuroprotection of Verbascoside in Alzheimer’s Disease Mediated through Mitigation of Neuroinflammation via Blocking NF-κB-p65 Signaling

The Neuroprotection of Verbascoside in Alzheimer’s Disease Mediated through Mitigation of Neuroinflammation via Blocking NF-κB-p65 Signaling

Alzheimer’s Amyloid-β Accelerates Cell Senescence and Suppresses the SIRT1/NRF2 Pathway in Human Microglial Cells

CD11c+ microglia promote white matter repair after ischemic stroke

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