Plasma exosomes impair microglial degradation of α-synuclein through V-ATPase subunit V1G1.

INTRODUCTION: Microglia are the main phagocytes in the brain and can induce neuroinflammation. Moreover, they are critical to alpha-synuclein (α-syn) aggregation and propagation. Plasma exosomes derived from patients diagnosed with Parkinson's disease (PD-exo) reportedly evoked α-syn aggregation and inflammation in microglia. In turn, microglia internalized and released exosomal α-syn, enhancing α-syn propagation. However, the specific mechanism through which PD-exo influences α-syn degradation remains unknown. METHODS: Exosomes were extracted from the plasma of patients with PD by differential ultracentrifugation, analyzed using electron microscopy (EM) and nanoparticle flow cytometry, and stereotaxically injected into the unilateral striatum of the mice. Transmission EM was employed to visualize lysosomes and autophagosomes in BV2 cells, and lysosome pH was measured with LysoSensor Yellow/Blue DND-160. Cathepsin B and D, lysosomal-associated membrane protein 1 (LAMP1), ATP6V1G1, tumor susceptibility gene 101 protein, calnexin, α-syn, ionized calcium binding adaptor molecule 1, and NLR family pyrin domain containing 3 were evaluated using quantitative polymerase chain reaction or western blotting, and α-syn, LAMP1, and ATP6V1G1 were also observed by immunofluorescence. Small interfering ribonucleic acid against V1G1 was transfected into BV2 cells and primary microglia using Lipofectamine® 3000. A PD mouse model was established via injection with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) into mice. A lentiviral-mediated strategy to overexpress ATP6V1G1 in the brain of MPTP-treated mice was employed. Motor coordination was assessed using rotarod and pole tests, and neurodegeneration in the mouse substantia nigra and striatum tissues was determined using immunofluorescence histochemical and western blotting of tyrosine hydroxylase. RESULTS: PD-exo decreased the expression of V1G1, responsible for the acidification of intra- and extracellular milieu. This impairment of lysosomal acidification resulted in the accumulation of abnormally swollen lysosomes and decreased lysosomal enzyme activities, impairing lysosomal protein degradation and causing α-syn accumulation. Additionally, V1G1 overexpression conferred the mice neuroprotection during MPTP exposure. CONCLUSION: Pathogenic protein accumulation is a key feature of PD, and compromised V-type ATPase dysfunction might participate in PD pathogenesis. Moreover, V1G1 overexpression protects against neuronal toxicity in an MPTP-based PD mouse model, which may provide opportunities to develop novel therapeutic interventions for PD treatment.

Mitochondria-lysosome-extracellular vesicles axis and nanotheranostics in neurodegenerative diseases.

The intricate functional interactions between mitochondria and lysosomes play a pivotal role in maintaining cellular homeostasis and proper cellular functions. This dynamic interplay involves the exchange of molecules and signaling, impacting cellular metabolism, mitophagy, organellar dynamics, and cellular responses to stress. Dysregulation of these processes has been implicated in various neurodegenerative diseases. Additionally, mitochondrial-lysosomal crosstalk regulates the exosome release in neurons and glial cells. Under stress conditions, neurons and glial cells exhibit mitochondrial dysfunction and a fragmented network, which further leads to lysosomal dysfunction, thereby inhibiting autophagic flux and enhancing exosome release. This comprehensive review synthesizes current knowledge on mitochondrial regulation of cell death, organelle dynamics, and vesicle trafficking, emphasizing their significant contributions to neurodegenerative diseases. Furthermore, we explore the emerging field of nanomedicine in the management of neurodegenerative diseases. The review provides readers with an insightful overview of nano strategies that are currently advancing the mitochondrial-lysosome-extracellular vesicle axis as a therapeutic approach for mitigating neurodegenerative diseases.

Circadian regulation of microglia function: Potential targets for treatment of Parkinson's Disease.

Circadian rhythms are involved in the regulation of many aspects of the body, including cell function, physical activity and disease. Circadian disturbance often predates the typical symptoms of neurodegenerative diseases and is not only a non-motor symptom, but also one of the causes of their occurrence and progression. Glial cells possess circadian clocks that regulate their function to maintain brain development and homeostasis. Emerging evidence suggests that the microglial circadian clock is involved in the regulation of many physiological processes, such as cytokine release, phagocytosis, and nutritional and metabolic support, and that disruption of the microglia clock may affect multiple aspects of Parkinson's disease, especially neuroinflammation and α-synuclein processes. Herein, we review recent advances in the circadian control of microglia function in health and disease, and discuss novel pharmacological interventions for microglial clocks in neurodegenerative disorders.

Astrocyte-to-neuron reprogramming and crosstalk in the treatment of Parkinson's disease.

Parkinson's disease (PD) is currently the fastest growing disabling neurological disorder worldwide, with motor and non-motor symptoms being its main clinical manifestations. The primary pathological features include a reduction in the number of dopaminergic neurons in the substantia nigra and decrease in dopamine levels in the nigrostriatal pathway. Existing treatments only alleviate clinical symptoms and do not stop disease progression; slowing down the loss of dopaminergic neurons and stimulating their regeneration are emerging therapies. Preclinical studies have demonstrated that transplantation of dopamine cells generated from human embryonic or induced pluripotent stem cells can restore the loss of dopamine. However, the application of cell transplantation is limited owing to ethical controversies and the restricted source of cells. Until recently, the reprogramming of astrocytes to replenish lost dopaminergic neurons has provided a promising alternative therapy for PD. In addition, repair of mitochondrial perturbations, clearance of damaged mitochondria in astrocytes, and control of astrocyte inflammation may be extensively neuroprotective and beneficial against chronic neuroinflammation in PD. Therefore, this review primarily focuses on the progress and remaining issues in astrocyte reprogramming using transcription factors (TFs) and miRNAs, as well as exploring possible new targets for treating PD by repairing astrocytic mitochondria and reducing astrocytic inflammation.

Efficacy and safety of 3-n-butylphthalide for the treatment of cognitive impairment: A systematic review and meta-analysis.

BACKGROUND: Current evidence for the efficacy of pharmacological treatment in improving cognitive function is absent. Recent studies have reported that 3-n-butylphthalide (NBP) has a positive effect on improving cognitive impairment; however, its clinical efficacy and safety is unclear. Therefore, we conducted a meta-analysis to assess its efficacy and safety for cognitive impairment. METHODS: We systematically searched the PubMed, EMBASE, Cochrane Library, Web of Science, and Scopus databases, and two reviewers independently screened and extracted the data from included studies. We synthesized the data using the Review Manager Software version 5.3. RESULTS: We included six randomized clinical trials (RCTs), encompassing 851 patients with cognitive impairment. The results showed that NBP improved cognitive impairment. Specifically, the clinical efficacy was better than that in the control group, with better performance in improving the Mini-Mental State Examination and the Montreal Cognitive Assessment scores, while decreasing the Alzheimer's Disease Assessment Scale-Cognitive subscale and the Clinician's Interview-Based Impression of Change plus caregiver input scores. There was no significant difference in the incidence of adverse events between both groups. CONCLUSION: The NBP is effective and safe in improving cognitive impairment; however, more high-quality RCTs are needed to confirm these findings.

The circadian clock protein Rev-erbα provides neuroprotection and attenuates neuroinflammation against Parkinson's disease via the microglial NLRP3 inflammasome.

BACKGROUND: Circadian disturbance is a common nonmotor complaint in Parkinson's disease (PD). The molecular basis underlying circadian rhythm in PD is poorly understood. Neuroinflammation has been identified as a key contributor to PD pathology. In this study, we explored the potential link between the core clock molecule Rev-erbα and the microglia-mediated NLR family pyrin domain-containing 3 (NLRP3) inflammasome in PD pathogenesis. METHODS: We first examined the diurnal Rev-erbα rhythms and diurnal changes in microglia-mediated inflammatory cytokines expression in the SN of MPTP-induced PD mice. Further, we used BV2 cell to investigate the impacts of Rev-erbα on NLRP3 inflammasome and microglial polarization induced by 1-methyl-4-phenylpyridinium (MPP+) and αsyn pre-formed fibril. The role of Rev-erbα in regulating microglial activation via NF-κB and NLRP3 inflammasome pathway was then explored. Effects of SR9009 against NLRP3 inflammasome activation, microgliosis and nigrostriatal dopaminergic degeneration in the SN and striatum of MPTP-induced PD mice were studied in detail. RESULTS: BV2 cell-based experiments revealed the role of Rev-erbα in regulating microglial activation and polarization through the NF-κB and NLRP3 inflammasome pathways. Circadian oscillation of the core clock gene Rev-erbα in the substantia nigra (SN) disappeared in MPTP-induced PD mice, as well as diurnal changes in microglial morphology. The expression of inflammatory cytokines in SN of the MPTP-induced mice were significantly elevated. Furthermore, dopaminergic neurons loss in the nigrostriatal system were partially reversed by SR9009, a selective Rev-erbα agonist. In addition, SR9009 effectively reduced the MPTP-induced glial activation, microglial polarization and NLRP3 inflammasome activation in the nigrostriatal system. CONCLUSIONS: These observations suggest that the circadian clock protein Rev-erbα plays an essential role in attenuating neuroinflammation in PD pathology, and provides a potential therapeutic target for PD treatment.

The pyrethroids metabolite 3-phenoxybenzoic acid induces dopaminergic degeneration.

Exposure to pyrethroids, a significant class of the most widely used agricultural chemicals, has been associated with an increased risk of Parkinson's disease (PD). However, although many different pyrethroids induce roughly the same symptoms of Parkinsonism, the underlying mechanisms remain unknown. To find the shared key features among these mechanisms, we focused on 3-phenoxybenzoic acid (3-PBA), a common and prominent metabolite of most pyrethroids produced via hydrolysis by CEs in mammals. To determine the contribution of 3-PBA to the initiation and progression of PD, we performed in vivo and in vitro experiments, respectively, and found that 3-PBA not only accumulates in murine brain tissues over time but also further induces PD-like pathologies (increased α-syn and phospho-S129, decreased TH) to the same or even greater extent than the precursor pyrethroid. A before-after study of PET-DAT in the same mice revealed that low concentrations of 3-PBA (0.5 mg/kg) could paradoxically cause DAT to increase (22.46% higher than pre-drug test). The intervention of DAT inhibitors and activators respectively alleviated and enhanced the dopaminergic toxicity of 3-PBA, indicating that 3-PBA interacts with DAT. In particular, low concentrations of 3-PBA increase the DAT, which in turn induces 3-PBA to enter the dopaminergic neurons to exert toxic effects. Finally, we described a mechanism underlying this potential role of 3-PBA in the pathological aggregation of α-syn. Specifically, 3-PBA was found to dysregulate C/EBP ß levels and further anomalously activate AEP in vivo and in vitro, accompanied by increased accumulation of pathologically cleaved α-syn (N103 fragments) and accelerated α-syn aggregation. All these results suggest that 3-PBA exposure could mimic the pathological and pathogenetic features of PD, showing that this metabolite is a key pathogenic compound in pyrethroid-related pathological effects and a possible dopamine neurotoxin. Additionally, our findings provide a crucial reference for the primary prevention of PD.

[Effect of acupuncture at Sifeng (EX-UE 10) on serum leptin in the child of anorexia].

OBJECTIVE: To observe effect of acupuncture at Sifeng (EX-UE 10) on serum leptin level in the child of anorexia, so as to reveal relation between changes of blood leptin level and anorexia of child. METHODS: Forty-two cases were randomly divided into 3 groups. The treatment group A (n = 15) were treated with acupuncture at Sifeng (EX-UE 10), once each week, 3 consecutive sessions constituting one course; the treatment group B (n = 15) were treated with acupuncture at Sifeng (EX-UE 10), once two weeks, 3 consecutive sessions constituting one course; the medication group (n = 12) were treated with oral administration of Lactein tablets, 1 - 2 tablets each time, 3 times each day, 4 weeks constituting one course. RESULTS: The effective rate was 93.3% in the treatment group A and 93.3% in the treatment group B, which were higher than that in the medication group, with a very significant differences (P < 0.01); after treatment, the serum leptin levels in the 3 groups had very significant changes (P < 0.01); the improvement of serum leptin levels in the treatment group A and B were better than that in the medication group (P < 0.05). CONCLUSION: Acupuncture at Sifeng (EX-UE 10) can promote secretion of serum leptin in the child of anorexia, and improve anorexia.