Chronic Caffeine Treatment Protects Against α-Synucleinopathy by Reestablishing Autophagy Activity in the Mouse Striatum

Luan, Yanan; Ren, Xiaojun; Zheng, Wu; Zeng, Zhenhai; Guo, Yingzi; Hou, Zhidong; Guo, Wei; Chen, Xingjun; Li, Fēi; Chen, Jiang‐Fan

doi:10.3389/fnins.2018.00301

Cited by 71 publications

(73 citation statements)

References 57 publications

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“…In fact, evidence shows that autophagy impairment is also involved in the degradation of internalized a-synuclein in the inflammatory pathogenesis of PD (45). Chronic caffeine treatment, as suggested by epidemiologic evidence, might confer a neuroprotective effect by blunting neuroinflammation in PD (46). Nonetheless, the underlying mechanism of autophagy in the inflammatory pathogenesis of PD is still unclear.…”

Section: Discussionmentioning

confidence: 99%

MicroRNA‐124 regulates the expression of p62/p38 and promotes autophagy in the inflammatory pathogenesis of Parkinson's disease

et al. 2019

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Parkinson's disease (PD) is a neurodegenerative disorder characterized by motor and nonmotor symptoms due to the selective loss of midbrain dopaminergic neurons. The evidence for a chronic inflammatory reaction mediated by microglial cells in the brain is particularly strong in PD. In our previous study, we have shown that brain‐specific microRNA‐124 (miR‐124) is significantly down‐regulated in the 1‐methy1‐4‐pheny1‐1,2,3,6‐tetrahydropyridine (MPTP)‐induced mouse model of PD and that it can also inhibit neuroinflammation during the development of PD. However, further investigation is required to understand whether the abnormal expression of miR‐124 regulates microglial activation. In this study, we found that the expression of sequestosome 1 (p62) and phospho‐p38 mitogen‐activated protein kinases (p‐p38) showed a significant increase in LPS‐treated immortalized murine microglial cell line BV2 cells in an MPTP‐induced mouse model of PD. Knockdown of p62 could suppress the secretion of proinflammatory cytokines and p‐p38 of microglia. Besides, inhibition of p38 suppressed the secretion of proinflammatory cytokines and promoted autophagy in BV2 cells. Moreover, our study is the first to identify a unique role of miR‐124 in mediating the microglial inflammatory response by targeting p62 and p38 in PD. In the microglial culture supernatant transfer model, the knockdown of p62 in BV2 cells prevented apoptosis and death of human neuroblastoma cell lines SH‐SY5Y (SH‐SY5Y) cells following microglia activation. In addition, the exogenous delivery of miR‐124 could suppress p62 and p‐p38 expression and could also attenuate the activation of microglia in the substantia nigra par compacta of MPTP‐treated mice. Taken together, our data suggest that miR‐124 could inhibit neuroinflammation during the development of PD by targeting p62, p38, and autophagy, indicating that miR‐124 could be a potential therapeutic target for regulating the inflammatory response in PD.—Yao, L., Zhu, Z., Wu, J., Zhang, Y., Zhang, H., Sun, X., Qian, C., Wang, B., Xie, L., Zhang, S., Lu, G. MicroRNA‐124 regulates the expression of p62/p38 and promotes autophagy in the inflammatory pathogenesis of Parkinson's disease. FASEB J. 33,8648–8665 (2019). http://www.fasebj.org

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Section: Discussionmentioning

confidence: 99%

MicroRNA‐124 regulates the expression of p62/p38 and promotes autophagy in the inflammatory pathogenesis of Parkinson's disease

et al. 2019

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“…Interestingly, chronic caffeine treatment has also been studied as a mTOR-independent autophagy enhancer. Given that human coffee consumption has been associated with a reduced risk of developing PD [334], caffeine could be inducing MA through activation of the adenosine receptor [335]. Chronic caffeine drinking during four months in human A53T α-syn fibrils-injected mice reversed α-syn-induced MA defects and decreased levels of phosphorylated α-syn in the injected site [335].…”

Section: Activation Of Ma and Lysosomal Functionmentioning

confidence: 99%

Targeting α-Synuclein for PD Therapeutics: A Pursuit on All Fronts

et al. 2020

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Parkinson’s Disease (PD) is characterized both by the loss of dopaminergic neurons in the substantia nigra and the presence of cytoplasmic inclusions called Lewy Bodies. These Lewy Bodies contain the aggregated α-synuclein (α-syn) protein, which has been shown to be able to propagate from cell to cell and throughout different regions in the brain. Due to its central role in the pathology and the lack of a curative treatment for PD, an increasing number of studies have aimed at targeting this protein for therapeutics. Here, we reviewed and discussed the many different approaches that have been studied to inhibit α-syn accumulation via direct and indirect targeting. These analyses have led to the generation of multiple clinical trials that are either completed or currently active. These clinical trials and the current preclinical studies must still face obstacles ahead, but give hope of finding a therapy for PD with time.

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“…Similarly, in the MPP+-treated SH-SY5Y cells, caffeine activated PI3K/Akt signaling and prevented apoptotic cell death by regulating the p-JNK and ERK signaling [151,152]. Caffeine also regulated PD-like pathology in α-synuclein-induced mice by modulating macroautophagy by improving the microtubule-associated protein LC-3, reducing the receptor protein sequestosome 1 (SQSTM1/p62) and chaperone-mediated autophagy (CMA), and by regulating the expression of LAMP2A [153]. To analyze whether the neuroprotective effects of caffeine are A2AR-dependent in MPTP-treated mice, the effects of caffeine were compared in wild-type (WT) and A2AR gene global knockout (A2A KO) mice, as well as in CNS cell type-specific (conditional) A2AR knockout (cKO) mice.…”

Section: Effects Of Caffeine Against Pd-related Neuroinflammation Andmentioning

confidence: 99%

Antioxidant and Neuroprotective Effects of Caffeine against Alzheimer’s and Parkinson’s Disease: Insight into the Role of Nrf-2 and A2AR Signaling

et al. 2020

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This paper reviews the results of studies conducted on the role of caffeine in the management of different neurological disorders, such as Parkinson’s disease (PD) and Alzheimer’s disease (AD). To highlight the potential role of caffeine in managing different neurodegenerative diseases, we identified studies by searching PubMed, Web of Science, and Google Scholar by scrutinizing the lists of pertinent publications. According to the collected overall findings, caffeine may reduce the elevated oxidative stress; inhibit the activation of adenosine A2A, thereby regulating the accumulation of Aβ; reduce the hyperphosphorylation of tau; and reduce the accumulation of misfolded proteins, such as α-synuclein, in Alzheimer’s and Parkinson’s diseases. The studies have suggested that caffeine has promising protective effects against different neurodegenerative diseases and that these effects may be used to tackle the neurological diseases and/or their consequences. Here, we review the ongoing research on the role of caffeine in the management of different neurodegenerative disorders, focusing on AD and PD. The current findings suggest that caffeine produces potent antioxidant, inflammatory, and anti-apoptotic effects against different models of neurodegenerative disease, including AD, PD, and other neurodegenerative disorders. Caffeine has shown strong antagonistic effects against the adenosine A2A receptor, which is a microglial receptor, and strong agonistic effects against nuclear-related factor-2 (Nrf-2), thereby regulating the cellular homeostasis at the brain by reducing oxidative stress, neuroinflammation, regulating the accumulation of α-synuclein in PD and tau hyperphosphorylation, amyloidogenesis, and synaptic deficits in AD, which are the cardinal features of these neurodegenerative diseases.

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Chronic Caffeine Treatment Protects Against α-Synucleinopathy by Reestablishing Autophagy Activity in the Mouse Striatum

Cited by 71 publications

References 57 publications

MicroRNA‐124 regulates the expression of p62/p38 and promotes autophagy in the inflammatory pathogenesis of Parkinson's disease

MicroRNA‐124 regulates the expression of p62/p38 and promotes autophagy in the inflammatory pathogenesis of Parkinson's disease

Targeting α-Synuclein for PD Therapeutics: A Pursuit on All Fronts

Antioxidant and Neuroprotective Effects of Caffeine against Alzheimer’s and Parkinson’s Disease: Insight into the Role of Nrf-2 and A2AR Signaling

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