BDNF reverses aging-related microglial activation

Wu, Shih Ying; Pan, Bo; Tsai, Sheng Feng; Chiang, Yen-Ting; Huang, Bu Miin; Mo, Fan; Kuo, Yu Min

doi:10.1186/s12974-020-01887-1

Cited by 103 publications

(84 citation statements)

References 51 publications

(67 reference statements)

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“…However, while many of these functions are ascribed to its production by neurons, microglial-derived BDNF has been shown to support learning-related synapse formation, and thus promote learning and memory [ 83 ]. BDNF levels have been found to be inversely related to microglial activation, as evidenced in vivo in aging and both in vivo and in vitro by BDNF treatment, reducing microglial activation; the production of HIV-associated neurocognitive disorders persist in the era of potent antiretroviral therapy, and CHARTER Study inflammatory mediators [ 84 ]. In a mouse microglial cell line, increases in the transcription factor KLF2, which we found to be decreased in microglia in meth-treated animals, increased microglial BDNF expression [ 85 ], further supporting the role of the upstream BDNF pathway in regulating microglial function.…”

Section: Discussionmentioning

confidence: 99%

Methamphetamine Increases the Proportion of SIV-Infected Microglia/Macrophages, Alters Metabolic Pathways, and Elevates Cell Death Pathways: A Single-Cell Analysis

Niu

Morsey

Lamberty

et al. 2020

Viruses

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Both substance use disorder and HIV infection continue to affect many individuals. Both have untoward effects on the brain, and the two conditions often co-exist. In the brain, macrophages and microglia are infectable by HIV, and these cells are also targets for the effects of drugs of abuse, such as the psychostimulant methamphetamine. To determine the interaction of HIV and methamphetamine, we isolated microglia and brain macrophages from SIV-infected rhesus monkeys that were treated with or without methamphetamine. Cells were subjected to single-cell RNA sequencing and results were analyzed by statistical and bioinformatic analysis. In the animals treated with methamphetamine, a significantly increased proportion of the microglia and/or macrophages were infected by SIV. In addition, gene encoding functions in cell death pathways were increased, and the brain-derived neurotropic factor pathway was inhibited. The gene expression patterns in infected cells did not cluster separately from uninfected cells, but clusters comprised of microglia and/or macrophages from methamphetamine-treated animals differed in neuroinflammatory and metabolic pathways from those comprised of cells from untreated animals. Methamphetamine increases CNS infection by SIV and has adverse effects on both infected and uninfected microglia and brain macrophages, highlighting the dual and interacting harms of HIV infection and drug abuse on the brain.

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Section: Discussionmentioning

confidence: 99%

Methamphetamine Increases the Proportion of SIV-Infected Microglia/Macrophages, Alters Metabolic Pathways, and Elevates Cell Death Pathways: A Single-Cell Analysis

Niu

Morsey

Lamberty

et al. 2020

Viruses

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“…ACE2 acts as the functional and host receptor for coronaviruses ( 1 ) and regulates normal brain function by stimulating brain-derived neurotrophic factor (BDNF) activity ( 36 ). BDNF plays a critical role in attenuating microglial activation ( 37 ) and neuronal inflammation ( 38 ), and low BDNF levels are associated with cognitive impairment in both human and animal studies ( 37 , 39 , 40 ). SARS-CoV-2 is now known to decrease ACE2-mediated BDNF activity ( 20 ), possibly by acting as a competitive angiotensin-II-antagonist via spike protein-ACE2 binding.…”

Section: Discussionmentioning

confidence: 99%

Impact of SARS-CoV-2 Infection on Cognitive Function: A Systematic Review

et al. 2021

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The prevalence and etiology of COVID-19's impact on brain health and cognitive function is poorly characterized. With mounting reports of delirium, systemic inflammation, and evidence of neurotropism, a statement on cognitive impairment among COVID-19 cases is needed. A substantial literature has demonstrated that inflammation can severely disrupt brain function, suggesting an immune response, a cytokine storm, as a possible cause of neurocognitive impairments. In this light, the aim of the present study was to summarize the available knowledge of the impact of COVID-19 on cognition (i.e., herein, we broadly define cognition reflecting the reporting on this topic in the literature) during the acute and recovery phases of the disease, in hospitalized patients and outpatients with confirmed COVID-19 status. A systematic review of the literature identified six studies which document the prevalence of cognitive impairment, and one which quantifies deficits after recovery. Pooling the samples of the included studies (total sample n = 644) at three standards of quality produced conservative estimates of cognitive impairment ranging from 43.0 to 66.8% prevalence in hospitalized COVID-19 patients only, as no studies which report on outpatients met criteria for inclusion in the main synthesis. The most common impairment reported was delirium and frequent reports of elevated inflammatory markers suggest etiology. Other studies have demonstrated that the disease involves marked increases in IL-6, TNFα, and IL-1β; cytokines known to have a profound impact on working memory and attention. Impairment of these cognitive functions is a characteristic aspect of delirium, which suggests these cytokines as key mediators in the etiology of COVID-19 induced cognitive impairments. Researchers are encouraged to assay inflammatory markers to determine the potential role of inflammation in mediating the disturbance of cognitive function in individuals affected by COVID-19.

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“…Besides neurons, TrkB was reported to be expressed in microglia. The activation of TrkB could inhibit aging-related activation of microglia and neuroin ammation [49]. In addition, BDNF supplement could attenuate ischemic stroke-induced activation of astrocytes, and reduce the expression of the pro-in ammation factors [50].…”

Section: Discussionmentioning

confidence: 99%

Dimeric Tacrine (10)-Hupyridone Effectively Combats Alzheimer’s Disease as A Multi-Target-Directed Ligand

Xuan

Yan

et al. 2021

Preprint

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Background Alzheimer’s disease (AD) is a neurodegenerative disorder with multiple pathological features. Therefore, multi-target-directed ligands (MTDLs) strategy has been developed to combat this disease. We have previously designed and synthesized dimeric tacrine (10)-hupyridone (A10E), a novel tacrine derivative with acetylcholinesterase (AChE) inhibition and brain-derived neurotrophic factor (BDNF) activation activity, by linking tacrine and a fragment of huperzine A. However, it was largely unknown whether A10E could act on other AD targets and produce cognition-enhancing ability in AD animal models. Methods Behavioral and biochemical methods were applied to evaluate multi-target cognitive-enhancing effects and mechanisms of A10E in APP/PS1 transgenic mice and β-amyloid (Aβ) oligomers-treated mice. The neuroprotective mechanisms of A10E were explored in SH-SY5Y cells. And the anti-aggregation effects of A10E on Aβ were directly investigated in vitro. Results A10E could prevent cognitive impairments in both APP/PS1 mice and Aβ oligomers-treated mice, with higher potency than tacrine and huperzine A. Moreover, A10E could effectively inhibit Aβ production and deposition, reduce neuroinflammation, enhance brain derived brain-derived neurotrophic factor (BDNF) expression, and elevate cholinergic neurotransmission in vivo. A10E, at nanomolar concentrations, could also inhibit Aβ oligomers-induced neurotoxicity via the activation of the TrkB/Akt pathway. Furthermore, Aβ oligomerization and fibrillization could be directly disrupted by A10E. Conclusion A10E could produce anti-AD neuroprotective effects via multi-target mechanisms, including the inhibition of Aβ aggregation, the activation of the BDNF/TrkB pathway, the reduction of neuroinflammation and the decrease of AChE activity. As MTDLs could produce additional benefits, such as overcoming the deficits of drug combination and enhancing the compliance of AD patients, our results suggested that A10E might be developed as a promising MTDL lead for the treatment of AD.

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BDNF reverses aging-related microglial activation

Cited by 103 publications

References 51 publications

Methamphetamine Increases the Proportion of SIV-Infected Microglia/Macrophages, Alters Metabolic Pathways, and Elevates Cell Death Pathways: A Single-Cell Analysis

Methamphetamine Increases the Proportion of SIV-Infected Microglia/Macrophages, Alters Metabolic Pathways, and Elevates Cell Death Pathways: A Single-Cell Analysis

Impact of SARS-CoV-2 Infection on Cognitive Function: A Systematic Review

Dimeric Tacrine (10)-Hupyridone Effectively Combats Alzheimer’s Disease as A Multi-Target-Directed Ligand

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