TREM2 modulates microglia phenotypes in the neuroinflammation of Parkinson's disease

Zhang, Youwen; Feng, Shujun; Nie, Kun; Li, Yan; Gao, Yuyuan; Gan, Rong Z.; Li, Bing; Sun, Xinfeng; Wang, Limin; Zhang, Yuhu

doi:10.1016/j.bbrc.2018.03.226

Cited by 111 publications

(97 citation statements)

References 30 publications

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“…The levels of CSF oligomeric alpha‐synuclein appeared to change particularly with lower concentrations at 3 hours after Nilotinib administration. These data are consistent with increased CSF levels of TREM2, which enhances the phagocytosis function of microglia and suppresses inflammation, suggesting that reduction in oligomeric alpha‐synuclein may be the result of increased phagocytosis. We previously demonstrated that Nilotinib promotes autophagic clearance of neurotoxic proteins and improves motor and cognitive symptoms in several models of neurodegeneration without evidence of increased inflammation .…”

Section: Discussionsupporting

confidence: 78%

Pharmacokinetics and pharmacodynamics of a single dose Nilotinib in individuals with Parkinson's disease

Pagán

Hebron

Wilmarth

et al. 2019

Pharmacology Res & Perspec

111

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Nilotinib is a broad‐based tyrosine kinase inhibitor with the highest affinity to inhibit Abelson (c‐Abl) and discoidin domain receptors ( DDR 1/2). Preclinical evidence indicates that Nilotinib reduces the level of brain alpha‐synuclein and attenuates inflammation in models of Parkinson's disease ( PD ). We previously showed that Nilotinib penetrates the blood‐brain barrier ( BBB ) and potentially improves clinical outcomes in individuals with PD and dementia with Lewy bodies ( DLB ). We performed a physiologically based population pharmacokinetic/pharmacodynamic (pop PK / PD ) study to determine the effects of Nilotinib in a cohort of 75 PD participants. Participants were randomized (1:1:1:1:1) into five groups (n = 15) and received open‐label random single dose ( RSD ) 150:200:300:400 mg Nilotinib vs placebo. Plasma and cerebrospinal fluid ( CSF ) were collected at 1, 2, 3, and 4 hours after Nilotinib administration. The results show that Nilotinib enters the brain in a dose‐independent manner and 200 mg Nilotinib increases the level of 3,4‐Dihydroxyphenylacetic acid ( DOPAC ) and homovanillic acid ( HVA ), suggesting alteration to dopamine metabolism. Nilotinib significantly reduces plasma total alpha‐synuclein and appears to reduce CSF oligomeric: total alpha‐synuclein ratio. Furthermore, Nilotinib significantly increases the CSF level of triggering receptors on myeloid cells ( TREM )‐2, suggesting an anti‐inflammatory effect. Taken together, 200 mg Nilotinib appears to be an optimal single dose that concurrently reduces inflammation and engages surrogate disease biomarkers, including dopamine metabolism and alpha‐synuclein.

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Section: Discussionsupporting

confidence: 78%

Pharmacokinetics and pharmacodynamics of a single dose Nilotinib in individuals with Parkinson's disease

Pagán

Hebron

Wilmarth

et al. 2019

Pharmacology Res & Perspec

111

View full text Add to dashboard Cite

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“…Recent epidemiological and pathological evidences have suggested that inflammation participates in the process of dopaminergic neuron degeneration [5]. Anti-inflammatory strategies are currently being studied to limit neuronal deterioration in this disease [6].…”

Section: Introductionmentioning

confidence: 99%

Salidroside protected against MPP⁺‐induced Parkinson's disease in PC12 cells by inhibiting inflammation, oxidative stress and cell apoptosis

Zhou

Fang

et al. 2018

Biotech and App Biochem

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The present study aimed to investigate the protective effects of salidroside (SAL) on 1-methyl-4-phenylpyridinium (MPP + )-induced PC12 cell model for Parkinson's disease. PC12 cells were pretreated with SAL in different concentrations and then exposed to MPP + . To evaluate the effects of SAL on cytotoxicity, the survival rate was tested by the 3-(4,5-dimethylthiazol-2-yl)-2,5-dimethyltetrazolium bromide (MTT) assay and the apoptosis was tested via flow cytometry and Western blot. Reactive oxygen species (ROS), glutathione (GSH), and malondialdehyde (MDA) were detected to analyze the effects of SAL on oxidative stress. The mRNA and protein levels of inflammatory factors TNF-α and IL-1β were also determined by real-time quantitative polymerase chain reaction and Western blot. Pretreatment with SAL effectively relieved the MPP + cytotoxic effects and decreased the release of ROS production and inflammatory cytokines. SAL also inhibited apoptosis, suppressed MDA activity, and increased GSH levels in MPP + -treated PC12 cells. Moreover, the expression levels of caspase-9, caspase-3, and Bax were significantly decreased in the SAL treatment groups compared with the MPP + group, whereas Bcl-2 expression was significantly increased in the SAL treatment groups. In summary, the overall results suggested that SAL have neuroprotective effects on the MPP + -induced PC12 cell model by inhibiting inflammation, oxidative stress, and cell apoptosis. SAL may be a potential active product to protect against Parkinson's disease.

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“…Although recently recognized as an overly simplified classification, microglia may assume one of two phenotypes: M1 or M2(Zhang et al . ). M1 microglia are associated with inflammatory cytokines, such as TNF‐α, and increased neurodegeneration.…”

mentioning

confidence: 97%

Alterations in brain TREM2 and Amyloid‐β levels are associated with neurocognitive impairment in HIV‐infected persons on antiretroviral therapy

Fields

Spencer

Swinton

et al. 2018

Journal of Neurochemistry

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Neuroinflammation is a common pathological correlate of HIV-associated neurocognitive disorders (HAND) in individuals on antiretroviral therapy (ART). Triggering receptor expressed on myeloid cells 2 (TREM2) regulates neuroinflammation, clears extracellular Amyloid (A)-β, surveys for damaged neurons, and orchestrates microglial differentiation. TREM2 has not been studied in HIV+ brain tissues. In this retrospective study, we investigated TREM2 expression levels and localization to microglia, Aβ protein levels, and tumor necrosis factor (TNF)-α transcript levels in the frontal cortices of 52 HIV+ decedents. All donors had been on ART; 14 were cognitively normal (CN), 17 had an asymptomatic neurocognitive impairment (ANI), and 21 had a minor neurocognitive disorder (MND). Total TREM2 protein levels were increased in the soluble and decreased in the membrane-enriched fractions of MND brain tissues compared to CN; however, brains from MND Hispanics showed the most robust alterations in TREM2 as well as significantly increased TNF-α mRNA and Aβ levels when compared to CN Hispanics. Significant alterations in the expression of total TREM2 protein and transcripts for TNF-α were not observed in non-Hispanics, despite higher levels of Aβ in the non-Hispanic CN group compared to the non-Hispanic MND groups. These findings show that decreased and increased TREM2 in membrane-bound fractions and in soluble-enriched fractions, respectively, is associated with increased Aβ and neuroinflammation in this cohort of HIV+ brains, particularly those identifying as Hispanics. These findings suggest a role for TREM2 in the brain of HIV+ individuals may deserve more investigation as a biomarker for HAND and as a possible therapeutic target. Open Data: Materials are available on https://cos.io/our-services/open-science-badges/ https://osf.io/93n6m/.

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TREM2 modulates microglia phenotypes in the neuroinflammation of Parkinson's disease

Cited by 111 publications

References 30 publications

Pharmacokinetics and pharmacodynamics of a single dose Nilotinib in individuals with Parkinson's disease

Pharmacokinetics and pharmacodynamics of a single dose Nilotinib in individuals with Parkinson's disease

Salidroside protected against MPP⁺‐induced Parkinson's disease in PC12 cells by inhibiting inflammation, oxidative stress and cell apoptosis

Alterations in brain TREM2 and Amyloid‐β levels are associated with neurocognitive impairment in HIV‐infected persons on antiretroviral therapy

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TREM2 modulates microglia phenotypes in the neuroinflammation of Parkinson's disease

Cited by 111 publications

References 30 publications

Pharmacokinetics and pharmacodynamics of a single dose Nilotinib in individuals with Parkinson's disease

Pharmacokinetics and pharmacodynamics of a single dose Nilotinib in individuals with Parkinson's disease

Salidroside protected against MPP+‐induced Parkinson's disease in PC12 cells by inhibiting inflammation, oxidative stress and cell apoptosis

Alterations in brain TREM2 and Amyloid‐β levels are associated with neurocognitive impairment in HIV‐infected persons on antiretroviral therapy

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Salidroside protected against MPP⁺‐induced Parkinson's disease in PC12 cells by inhibiting inflammation, oxidative stress and cell apoptosis