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Curcumin Ameliorates Neuroinflammation, Neurodegeneration, and Memory Deficits in p25 Transgenic Mouse Model that Bears Hallmarks of Alzheimer's Disease.

ABSTRACT: Several studies have indicated that neuroinflammation is indeed associated with neurodegenerative disease pathology. However, failures of recent clinical trials of anti-inflammatory agents in neurodegenerative disorders have emphasized the need to better understand the complexity of the neuroinflammatory process in order to unravel its link with neurodegeneration. Deregulation of Cyclin-dependent kinase 5 (Cdk5) activity by production of its hyperactivator p25 is involved in the formation of tau and amyloid pathology reminiscent of Alzheimer's disease (AD). Recent studies show an association between p25/Cdk5 hyperactivation and robust neuroinflammation. In addition, we recently reported the novel link between the p25/Cdk5 hyperactivation-induced inflammatory responses and neurodegenerative changes using a transgenic mouse that overexpresses p25 (p25Tg). In this study, we aimed to understand the effects of early intervention with a potent natural anti-inflammatory agent, curcumin, on p25-mediated neuroinflammation and the progression of neurodegeneration in p25Tg mice. The results from this study showed that curcumin effectively counteracted the p25-mediated glial activation and pro-inflammatory chemokines/cytokines production in p25Tg mice. Moreover, this curcumin-mediated suppression of neuroinflammation reduced the progression of p25-induced tau/amyloid pathology and in turn ameliorated the p25-induced cognitive impairments. It is widely acknowledged that to treat AD, one must target the early-stage of pathological changes to protect neurons from irreversible damage. In line with this, our results demonstrated that early intervention of inflammation could reduce the progression of AD-like pathological outcomes. Moreover, our data provide a rationale for the potential use of curcuminoids in the treatment of inflammation associated neurodegenerative diseases.

SUBMITTER: Sundaram JR

PROVIDER: S-EPMC8092919 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundParkinson's disease (PD) is a common neurodegenerative disorder, accompanied by motor deficits as well as gastrointestinal dysfunctions. Recent studies have proved that the disturbance of gut microbiota and metabolism contributes to the pathogenesis of PD; however, the mechanisms underlying these effects have yet to be elucidated. Curcumin (CUR) has been reported to provide neuroprotective effects on neurological disorders and modulate the gut flora in intestinal-related diseases. Therefore, it is of significant interest to investigate whether CUR could exert a protective effect on PD and whether the effect of CUR is dependent on the intestinal flora and subsequent changes in metabolites.MethodsIn this study, we investigated the neuroprotective effects of CUR on a mouse model of PD induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). 16S rRNA sequencing was performed to explore the profile of the gut microbiota among controls, MPTP-treated mice and CUR-treated mice. Then, antibiotic treatment (ABX) and fecal microbiota transplantation (FMT) experiments were conducted to examine the role of intestinal microbes on the protective effects of CUR in PD mice. Furthermore, ultra-high-performance liquid chromatography-mass spectrometry (UHPLC-MS)-based metabolomics analysis was used to identify the landscape of the CUR-driven serum metabolome. Finally, Pearson's analysis was conducted to investigate correlations between the gut flora-metabolite axis and CUR-driven neuroprotection in PD.ResultsOur results showed that CUR intervention effectively improved motor deficits, glial cell activation, and the aggregation of α-synuclein (α-syn) in MPTP-treated mice. 16S rRNA sequencing showed elevated abundances of Muribaculaceae, Lactobacillaceae, Lachnospiraceae and Eggerthellaceae but depleted abundances of Aerococcaceae and Staphylococcaceae in CUR-treated mice when compared with MPTP mice. ABX and FMT experiments further confirmed that the gut microbiota was required for CUR-induced protection in PD mice. Serum metabolomics analysis showed that CUR notably upregulated the levels of tyrosine, methionine, sarcosine and creatine. Importantly, strong correlations were identified among crucial taxa (Aerococcaceae, Staphylococcaceae, Muribaculaceae, Lactobacillaceae, Lachnospiraceae and Eggerthellaceae), pivotal metabolites (tyrosine, methionine, sarcosine and creatine) and the motor function and pathological results of mice. CUR treatment led to a rapid increase in the brain levels of tyrosine and levodopa (dopa) these changes were related to the abundances of Lactobacillaceae and Aerococcaceae.ConclusionsCUR exerts a protective effect on the progression of PD by modulating the gut microbiota-metabolite axis. Lactobacillaceae and Aerococcaceae, along with key metabolites such as tyrosine and dopa play a dominant role in CUR-associated neuroprotection in PD mice. Our findings offer unique insights into the pathogenesis and potential treatment of PD.

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Curcumin Ameliorates Neuroinflammation, Neurodegeneration, and Memory Deficits in p25 Transgenic Mouse Model that Bears Hallmarks of Alzheimer's Disease.

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