Molecular Neurobiology最新文献

The ability of atraric acid (AA), a lichen-derived metabolite with anti-inflammatory/antioxidant properties, to protect against obesity-associated neurological dysfunctions was investigated given the role of obesity in triggering neuroinflammation via free fatty acids. Model mice were fed a high-fat diet (HFD) for 12 weeks, and HT22 neurons were exposed to oleic acid/palmitic acid (OA/PA). A variety of experimental techniques, including CCK8, H&E staining, Nissl staining, QPCR, and behavioral tests (open field, elevated plus maze, and Morris water maze), have been used to assess cognitive/anxiety phenotypes. Molecular analyses, including ELISAs (TNF-α/IL-6/GM-CSF), biochemical assays (oxidative stress markers), immunofluorescence/Western blotting, H₂DCFDA-based ROS quantification, and 3-methyladenine (3MA) autophagy blockade, were also performed. The results revealed that AA effectively alleviated anxiety- and depression-like behaviors in HFD-fed mice, as demonstrated by the results of open field and elevated plus-maze tests. AA also significantly mitigated the cognitive decline observed in behavioral assessments, such as the Morris water maze test. Furthermore, AA protected against structural damage and neuronal death in the hippocampal CA1 region. ELISAs and biochemical assays revealed that increasing concentrations of atraric acid significantly reduced the levels of the neuronal injury markers NSE and S100β, as well as the proinflammatory cytokines TNF-α, IL-6, and GM-CSF. Western blot analysis confirmed that AA activated autophagy via the mTOR signaling pathway, thereby reducing oxidative stress, attenuating neuroinflammation, and ultimately improving cognitive impairment in mice. In conclusion, this study demonstrated that the protective effect of AA against HFD-induced cognitive impairment is associated with the activation of autophagy, a reduction in oxidative stress, and the alleviation of neuroinflammation. Our findings demonstrate the neuroprotective properties of atraric acid in preclinical models, providing a rationale for further investigation as a potential candidate for treating cognitive dysfunction.

Chronic alcohol drinking increases susceptibility to cognitive impairment; however, the underlying mechanisms remain unclear. In this study, we investigated the effects of chronic alcohol drinking on working and recognition memory in a Marchigian Sardinian alcohol-preferring (msP) rat line. Due to interest in insulin-based medications for alcohol use disorder, we examined insulin/insulin-like growth factor 1 (IGF-1) genes in the prelimbic (PL) and infralimbic (IL) medial prefrontal cortex, a region linked to alcohol dependence and cognition. Male and female msPs received access to alcohol (20% v/v) and water (H₂O) using a group-housed 2 bottle-choice drinking paradigm for several weeks, while controls received H₂O only. After five weeks, the radial arm maze and novel object recognition tasks evaluated working and recognition memory. At the end of the study, genes encoding for insulin/IGF-1, their receptors, and downstream effectors were assessed in the PL, IL and hippocampus CA1 (CA1), three main regions involved in working and recognition memory processing. Genes regulating brain plasticity were also assessed. Females consumed more alcohol than males. Chronic alcohol exposure selectively impaired recognition memory in males, while working memory remained unaffected in both sexes. Chronic alcohol exposure altered transcription of insulin/IGF-1 signaling components. In females, chronic alcohol reduced Ins transcript levels in the IL, while increasing Insr expression in the PL, but not in the CA1. In males, chronic alcohol reduced Igf1r transcript levels in the IL, but not PL or CA1. Across both sexes and all regions, chronic alcohol decreased Irs2, a downstream effector of insulin/IGF-1, transcript levels. Lastly, we observed some alterations in genes linked to memory and plasticity including Bdnf, TrkB, Psd95, and Pkmζ. Together, these findings suggest that chronic alcohol drinking impairs recognition memory in males, while broadly disrupting metabolic and plasticity-associated genes in the mPFC and CA1.

Per- and polyfluoroalkyl substances (PFAS), a group of persistent organic pollutants characterized by C-F bonds, have been detected in various human samples and tend to accumulate in the brain, posing potential neurotoxic risks. Gaining insights into PFAS-induced neurotoxicity and its underlying molecular mechanisms is crucial for assessing health risks associated with human exposure, however, research in this area remains limited. This review summarizes studies on the processes of PFAS uptake, accumulation, and mechanisms within the brain: disruption of the blood-brain barrier (BBB) via tight junction interference and reliance on transporter proteins located at the BBB. Accumulation of PFAS in the brain has been linked to neurotoxic effects in the central nervous system (CNS), including attention-deficit/hyperactivity disorder (ADHD) in children and Parkinson's or Alzheimer's disease in older adults. Mechanistic investigations into neurotoxicity have focused on alterations in neurotransmitter levels, mitochondrial dysfunction, neuronal damage, and thyroid hormone signaling pathways. This study offers foundational support for a broader understanding of adverse neurological toxicity, mechanisms of brain penetration, and increased risks of behavioral and cognitive disorders due to PFAS exposure in humans.

Parkinson's disease (PD) is a neurodegenerative condition marked by significant motor impairments, resulting from extensive loss of dopaminergic neurons and abnormal protein aggregation. One of the early features of PD is disrupted mitochondrial dynamics, which arises from imbalances in cellular energy regulation. Therapeutic strategies that mitigate the mitochondrial dysfunction and enhance mitochondrial performance offer neuroprotection in PD. To delve into the role of mitochondrial function, we employed the synthetic PGC-1α activator ZLN005 to improve PD outcomes. In cellular PD model, we performed western blotting and immunofluorescence assays to assess disease-specific markers, including tyrosine hydroxylase and proteins related to mitochondrial biogenesis and regulation. Mitochondrial function was further evaluated using MitoTracker and ROS detection. We further investigated ZLN005 in a sub-acute MPTP mouse model. Motor performance was assessed, and subsequently, molecular analyses were conducted. Our findings revealed that ZLN005 significantly reduced MPP⁺/MPTP-induced neurotoxicity, improved motor deficits, and maintained the expression of PGC-1α, tyrosine hydroxylase, and other key mitochondrial markers involved in DNA replication and mitophagy. Notably, proteins that enhance PGC-1α transcription, including SIRT1, were also upregulated. In addition, the expression of mitochondrial fusion proteins increased, a pattern supported by elevated levels of other transcriptional regulators. Imaging and flow cytometry further confirmed that PGC-1α activation improved mitochondrial integrity and reduced oxidative stress. These results provide preliminary insights into the potential therapeutic role of PGC-1α activator in PD. ZLN005 has a neuroprotective effect in PD, which is elaborated by PGC-1α activator regulating the mitochondrial quality control system.

Parkinson's disease (PD) is a significant global health issue, ranking as the second most prevalent neurodegenerative disorder after Alzheimer's disease. Research suggests that changes in the gut microbiota may occur before the onset of the motor symptoms of PD. This study seeks to conduct a systematic review (PROSPERO registration ID: CRD420251118297) to explore the mechanistic exploration and biomarker identification of gut microbiota in PD. The research involved a comprehensive literature search across PubMed, Scopus, and Web of Science databases up to August 2022 using a combination of Medical Subject Heading (MeSH) terms for Parkinson's disease, gut microbiota, and metabolites. Eligible studies included in vivo and in vitro investigations focusing on the metabolite levels produced by the gut microbiota in PD patients. Data extraction was performed by two researchers using Microsoft Excel Software. The Newcastle-Ottawa Scale (NOS) was used to assess the risk of bias. The certainty of the evidence was evaluated using the GRADE framework. The review encompassed 39 selected studies, comprising data from over 3000 participants. Approximately two-thirds of the studies reported a reduction in short-chain fatty acids (SCFAs), notably butyrate and acetate, while almost half reported increased trimethylamine N-oxide (TMAO) levels or altered amino acid and bile acid pathways. Key findings emphasized the comparison of microbiomes in PD patients and healthy controls, highlighting metabolic pathway alterations and their implications for PD development. Studies also delved into the role of inflammation in PD progression, exploring the connection between inflammatory factors and the microbiota. Additionally, the present study examined the influence of PD medications on gut microbiota. This systematic review highlights the potential involvement of gut microbiota in modulating the gut-brain axis in PD. Observed associations suggest links between altered metabolite production, pro-inflammatory states, increased gut permeability, and changes in LPS and α-synuclein dynamics. However, these relationships remain largely correlative, and causal mechanisms are yet to be established. Further longitudinal and mechanistic studies are warranted to confirm these observations and explore their clinical relevance.

A rapid, accurate diagnostic test for amyotrophic lateral sclerosis (ALS) would reduce diagnostic delays and improve patient outcomes. We extracted eight circulating miRNAs from 788 blood plasma samples and analyzed them using qPCR for ALS diagnostic accuracy. The biomarker parameters were established previously using 449 individual blood samples and applied prospectively to an independent cohort for validation of a predictive model. The primary outcome was ALS classification accuracy as measured by diagnostic sensitivity, specificity, positive and negative predictive values (PPV, NPV), and area under the curve (AUC). The secondary outcome was comparative fold-regulation values determined prior to data collection. The diagnostic test had an AUC of 0.98 (95% CI 0.97-0.99), with 97% sensitivity (95% CI 96-98), 93% specificity (95% CI 90-96), 93% PPV (95% CI 91-96), and 97% NPV (95% CI 96-98). The fold-regulation values exceeded or were equal to prior calculated values. Streamlined methods resulted in higher diagnostic accuracy, cut both assay time and cost, reduced technical barriers, and enhances the feasibility for widespread clinical adoption. The high accuracy of this diagnostic biomarker suggests that continued evaluation is warranted.

The glymphatic system is a glial-dependent network responsible for the clearance of waste products from the brain through cerebrospinal fluid (CSF) circulation. This process, which involves astrocytes and the water channel AQP4, facilitates the removal of harmful proteins like β-amyloid and tau, making it crucial in neurodegenerative diseases such as Alzheimer's (AD) and Parkinson's disease (PD). AQP4 dysfunction has been linked to the accumulation of these proteins and related pathologies. This study aimed to investigate the association between AQP4 gene polymorphisms (rs2075575, rs162009, and rs335929) and PD in an Italian cohort, consisting of 380 individuals with PD enrolled in a rehabilitation protocol and 461 healthy controls. The analysis found no significant correlation between the selected AQP4 single nucleotide polymorphisms (SNPs) and PD risk. However, the rs162009 AA genotype was associated with a lower risk of developing REM sleep behavior disorder (RBD) symptoms in PD patients, while rs2075575 was linked to hallucinations in these individuals. These findings suggest a potential role for AQP4 polymorphisms in sleep disturbances and psychotic symptoms in PD, but further research is needed to confirm these results and understand the complex interactions between the glymphatic system and PD pathophysiology.

Neuronal cholecystokinin (CCK) is the most abundant neuropeptide in the mammalian brain and serves as a critical neuromodulator regulating the physiological states of animals. Previous research on CCK primarily focused on its roles in digestive function, satiety regulation, and emotional modulation, while its involvement in the development of brain diseases remains largely unexplored. Interestingly, recent studies have revealed that CCK-2 receptor antagonists have significant effects on neural modulation, suggesting a potential strategy for the treatment of brain disorders such as Alzheimer's disease, depression, and motor neuron disease, among others. To elucidate the neural effects of CCK on the progression of neurological disorders, we review the available evidence on the neuropeptide CCK in brain diseases at multiple levels and propose novel and complementary approaches to the treatment of brain diseases based on recent developments.

Tauroursodeoxycholic acid (TUDCA) shows therapeutic potential for neuroinflammation and related neuropsychiatric disorders. However, the intrinsic mechanism by which TUDCA counteracts microglial activation and neuroinflammation has not been clarified. In this study, the epigenetic mechanism through which TUDCA regulates inducible nitric oxide synthase (iNOS) generation to antagonize microglial activation was investigated in lipopolysaccharide (LPS)-treated microglial BV-2 cells and mice. The results confirmed the inhibitory effects of TUDCA on LPS-induced iNOS overgeneration, oxidative stress and microglial activation in BV-2 cells. Mechanistically, TUDCA inhibited the recruitment of NF-κB and the histone acetyltransferase p300 to the iNOS gene promoter and reduced the enrichment of histone H3 lysine 14 acetylation (H3K14ac), but not H3K9ac in LPS-stimulated BV-2 cells. Moreover, TUDCA inhibited the binding and co-localization of NF-κB and p300, and reduced the p300-bound H3K14ac in LPS-stimulated BV-2 cells. Although the bile acid nuclear receptor farnesoid X receptor (FXR) has been reported to inhibit the NF-κB signaling pathway, its content hardly changed among the groups, indicating TUDCA's effects independent of FXR in this context. In addition, molecular docking predicted specific binding between TUDCA and p300. Consistent with the cellular findings, TUDCA alleviated neuroinflammation and behavioral abnormalities in LPS-treated mice. TUDCA also attenuated microglial activation in the hippocampus and reduced brain H3K14ac level. In conclusion, TUDCA inhibited NF-κB/p300 activity and decreased H3K14ac enrichment at the iNOS gene promoter, thereby attenuating microglial activation in both LPS-treated BV-2 cells and mice.

Neuroinflammation is recognized as a key contributor to the pathogenesis and progression of amyotrophic lateral sclerosis (ALS), with dysregulated innate immune activation implicated in exacerbating neuronal injury. However, the molecular mechanisms by which macrophages contribute to neurodegeneration in motor neurons harboring TAR DNA-binding protein 43 (TDP-43) mutations are not fully understood. M1 macrophages were generated from the bone marrow of Irf5 knockout or wild-type mice and co-cultured with the NSC34 motor neuron-like cell line overexpressing the C-terminal fragment of TDP-43 (TDP-25) using a Transwell system. Mitochondrial alterations, and apoptosis were evaluated through Western blotting, flow cytometry, and transmission electron microscopy. IMD-0354 mitigated mitochondrial dysfunction and apoptosis induced by TDP-25 exposure. This neuroprotective effect was attenuated in the presence of pro-inflammatory macrophages. Notably, the absence of Irf5 expression in macrophages amplified the protective efficacy of IMD-0354. Irf5 expression in macrophages may modulate the therapeutic efficacy of IMD-0354 in the context of TDP-43-associated proteinopathy, indicating a potential target for enhancing treatment strategies in ALS-related neurodegeneration through inhibiting inflammation.