Microglial polarization: novel therapeutic mechanism against Alzheimer’s disease

Yao, Kai; Zu, Hengbing

doi:10.1007/s10787-019-00613-5

Cited by 118 publications

(89 citation statements)

References 117 publications

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“…However, they have a dual role which remains contentious. Microglia can exhibit two phenotypes: M1 (proinflammatory) and M2 (anti-inflammatory) (Yao and Zu, 2019). Microglial cells are able to remove Aβ deposits in the early stages of a lesion but fail to do so as the disease progresses.…”

Section: Discussionmentioning

confidence: 99%

RETRACTED: Resveratrol Preincubation Enhances the Therapeutic Efficacy of hUC-MSCs by Improving Cell Migration and Modulating Neuroinflammation Mediated by MAPK Signaling in a Mouse Model of Alzheimer’s Disease

Wang

et al. 2020

Front. Cell. Neurosci.

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Human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) are promising for the treatment of Alzheimer's disease (AD). However, their low rate of migration and survival in the brain limit their clinical applicability. This study is designed to improve the therapeutic potential of hUC-MSCs by preincubating them with resveratrol, a natural polyphenol capable of regulating cell destiny. Herein, we demonstrate that resveratrol preincubation enhances the migration of hUC-MSCs in vitro, as well as their survival and homing into the hippocampus of AD mice in vivo. Moreover, resveratrol-primed MSCs were better able to inhibit amyloid-β peptide (Aβ) deposition, Tau hyperphosphorylation, and oxidative stress, all while improving learning and memory. Notably, we found that hUC-MSCs inhibited neuroinflammation by reacting with astrocytes and microglial cells and suppressing mitogen-activated protein kinases (MAPKs), extracellular signal kinases (ERK), p38 kinases (p38), and c-Jun N-terminal kinases (JNK) signaling pathways in the hippocampus of AD mice. Furthermore, resveratrol pretreatment enhanced these effects. Conclusively, the current study revealed that resveratrol preconditioning protected hUC-MSCs against the hostile microenvironment characteristic of AD and enhanced their viability and homing into the brain of AD mice. The use of resveratrol-pretreated hUC-MSCs is thereby proposed to be a promising therapy for AD.

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Section: Discussionmentioning

confidence: 99%

RETRACTED: Resveratrol Preincubation Enhances the Therapeutic Efficacy of hUC-MSCs by Improving Cell Migration and Modulating Neuroinflammation Mediated by MAPK Signaling in a Mouse Model of Alzheimer’s Disease

Wang

et al. 2020

Front. Cell. Neurosci.

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“…Novel technologies, including RNA-seq analysis, have revealed that microglial transcriptomic and proteomic profiles could be drastically different based on criteria such as the region, time, disease, and state [ 31 ]. Simple classification as M1 or M2 phenotype does not accurately describe the heterogeneity of microglia; however, this classification is still accepted and used, especially in the clinical treatment of stroke and neurodegenerative disease [ 32 , 33 ]. Therefore, this simplified classification method is still instructive.…”

Section: Discussionmentioning

confidence: 99%

Sestrin2 regulates microglia polarization through mTOR-mediated autophagic flux to attenuate inflammation during experimental brain ischemia

Song

et al. 2020

J Neuroinflammation

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Background Neuroinflammation is the major pathogenesis of cerebral ischemia. Microglia are activated and polarized to either the pro-inflammatory M1 phenotype or anti-inflammatory M2 phenotype, which act as a critical mediator of neuroinflammation. Sestrin2 has pro-survival properties against ischemic brain injury. However, whether sestrin2 has an anti-inflammatory function by shifting microglia polarization and its underlying mechanism is unknown. Methods Adult male C57BL/6 mice (N = 108) underwent transient middle cerebral artery occlusion (tMCAO) and were treated with exogenous sestrin2. Neurological deficit scores and infarct volume were determined. Cell apoptosis was examined by TUNEL staining and Western blotting. The expression of inflammatory mediators, M1/M2-specific markers, and signaling pathways were detected by reverse transcription-polymerase chain reaction, immunostaining, and Western blotting. To explore the underlying mechanism, primary neurons were subjected to oxygen-glucose deprivation (OGD) and then treated with oxygenated condition medium of BV2 cells incubated with different doses of sestrin2. Results Sestrin2 attenuated the neurological deficits, infarction volume, and cell apoptosis after tMCAO compared to those in the control (p < 0.05). Sestrin2 had an anti-inflammatory effect and could suppress M1 microglia polarization and promote M2 microglia polarization. Condition medium from BV2 cells cultured with sestrin2 reduced neuronal apoptosis after OGD in vitro. Furthermore, we demonstrated that sestrin2 drives microglia to the M2 phenotype by inhibiting the mammalian target of rapamycin (mTOR) signaling pathway and restoring autophagic flux. Conclusions Sestrin2 exhibited neuroprotection by shifting microglia polarization from the M1 to M2 phenotype in ischemic mouse brain, which may be due to suppression of the mTOR signaling pathway and the restoration of autophagic flux.

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“…During disease progression, however, the M2 phenotype appears to undergo polarization into an M1 phenotype, resulting in the overproduction of neurotoxic factors. Indeed, in all stages of AD, significant aggregation of M1 microglia has been observed surrounding neurofibrillary tangles (Sheffield et al, 2000;Yao and Zu, 2020). M1 microglia not only release neurotoxic factors but have also been shown to downregulate or even block neuroprotective mechanisms involved in phagocytosis of Aβ (Yamamoto et al, 2008).…”

Section: The Old Man and The Alzheimer's Diseasementioning

confidence: 99%

Going the Extra (Synaptic) Mile: Excitotoxicity as the Road Toward Neurodegenerative Diseases

Armada‐Moreira

Gomes

Pina

et al. 2020

Front. Cell. Neurosci.

199

128

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Excitotoxicity is a phenomenon that describes the toxic actions of excitatory neurotransmitters, primarily glutamate, where the exacerbated or prolonged activation of glutamate receptors starts a cascade of neurotoxicity that ultimately leads to the loss of neuronal function and cell death. In this process, the shift between normal physiological function and excitotoxicity is largely controlled by astrocytes since they can control the levels of glutamate on the synaptic cleft. This control is achieved through glutamate clearance from the synaptic cleft and its underlying recycling through the glutamate-glutamine cycle. The molecular mechanism that triggers excitotoxicity involves alterations in glutamate and calcium metabolism, dysfunction of glutamate transporters, and malfunction of glutamate receptors, particularly N-methyl-D-aspartic acid receptors (NMDAR). On the other hand, excitotoxicity can be regarded as a consequence of other cellular phenomena, such as mitochondrial dysfunction, physical neuronal damage, and oxidative stress. Regardless, it is known that the excessive activation of NMDAR results in the sustained influx of calcium into neurons and leads to several deleterious consequences, including mitochondrial dysfunction, reactive oxygen species (ROS) overproduction, impairment of calcium buffering, the release of pro-apoptotic factors, among others, that inevitably contribute to neuronal loss. A large body of evidence implicates NMDAR-mediated excitotoxicity as a central mechanism in the pathogenesis of many neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), and epilepsy. In this review article, we explore different causes and consequences of excitotoxicity, discuss the involvement of NMDAR-mediated

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Microglial polarization: novel therapeutic mechanism against Alzheimer’s disease

Cited by 118 publications

References 117 publications

RETRACTED: Resveratrol Preincubation Enhances the Therapeutic Efficacy of hUC-MSCs by Improving Cell Migration and Modulating Neuroinflammation Mediated by MAPK Signaling in a Mouse Model of Alzheimer’s Disease

RETRACTED: Resveratrol Preincubation Enhances the Therapeutic Efficacy of hUC-MSCs by Improving Cell Migration and Modulating Neuroinflammation Mediated by MAPK Signaling in a Mouse Model of Alzheimer’s Disease

Sestrin2 regulates microglia polarization through mTOR-mediated autophagic flux to attenuate inflammation during experimental brain ischemia

Going the Extra (Synaptic) Mile: Excitotoxicity as the Road Toward Neurodegenerative Diseases

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