Matrix metalloproteinase-9 inhibition prevents aquaporin-4 depolarization-mediated glymphatic dysfunction in Parkinson's disease.

INTRODUCTION: The glymphatic system offers a perivascular pathway for the clearance of pathological proteins and metabolites to optimize neurological functions. Glymphatic dysfunction plays a pathogenic role in Parkinson's disease (PD); however, the molecular mechanism of glymphatic dysfunction in PD remains elusive. OBJECTIVE: To explore whether matrix metalloproteinase-9 (MMP-9)-mediated ß-dystroglycan (ß-DG) cleavage is involved in the regulation of aquaporin-4 (AQP4) polarity-mediated glymphatic system in PD. METHODS: 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD and A53T mice were used in this study. The glymphatic function was evaluated using ex vivo imaging. TGN-020, an AQP4 antagonist, was administered to investigate the role of AQP4 in glymphatic dysfunction in PD. GM6001, an MMP-9 antagonist, was administered to investigate the role of the MMP-9/ß-DG pathway in regulating AQP4. The expression and distribution of AQP4, MMP-9, and ß-DG were assessed using western blotting, immunofluorescence, and co-immunoprecipitation. The ultrastructure of basement membrane (BM)-astrocyte endfeet was detected using transmission electron microscopy. Rotarod and open-field tests were performed to evaluate motor behavior. RESULTS: Perivascular influx and efflux of cerebral spinal fluid tracers were reduced in MPTP-induced PD mice with impaired AQP4 polarization. AQP4 inhibition aggravated reactive astrogliosis, glymphatic drainage restriction, and dopaminergic neuronal loss in MPTP-induced PD mice. MMP-9 and cleaved ß-DG were upregulated in both MPTP-induced PD and A53T mice, with reduced polarized localization of ß-DG and AQP4 to astrocyte endfeet. MMP-9 inhibition restored BM-astrocyte endfeet-AQP4 integrity and attenuated MPTP-induced metabolic perturbations and dopaminergic neuronal loss. CONCLUSION: AQP4 depolarization contributes to glymphatic dysfunction and aggravates PD pathologies, and MMP-9-mediated ß-DG cleavage regulates glymphatic function through AQP4 polarization in PD, which may provide novel insights into the pathogenesis of PD.

Disruption of Dopamine Homeostasis Associated with Alteration of Proteins in Synaptic Vesicles: A Putative Central Mechanism of Parkinson's Disease Pathogenesis.

Vestigial dopaminergic cells in PD have selectivity for a sub-class of hypersensitive neurons with the nigrostriatal dopamine (DA) tract. DA is modulated in pre-synaptic nerve terminals to remain stable. To be specific, proteins at DA release sites that have a function of synthesizing and packing DA in cytoplasm, modulating release and reingestion, and changing excitability of neurons, display regional discrepancies that uncover relevancy of the observed sensitivity to neurodegenerative changes. Although the reasons of a majority of PD cases are still indistinct, heredity and environment are known to us to make significant influences. For decades, genetic analysis of PD patients with heredity in family have promoted our comprehension of pathogenesis to a great extent, which reveals correlative mechanisms including oxidative stress, abnormal protein homeostasis and mitochondrial dysfunction. In this review, we review the constitution of presynaptic vesicle related to DA homeostasis and describe the genetic and environmental evidence of presynaptic dysfunction that increase risky possibility of PD concerning intracellular vesicle transmission and their functional outcomes. We summarize alterations in synaptic vesicular proteins with great involvement in the reasons of some DA neurons highly vulnerable to neurodegenerative changes. We generalize different potential targets and therapeutic strategies for different pathogenic mechanisms, providing a reference for further studies of PD treatment in the future. But it remains to be further researched on this recently discovered and converging mechanism of vesicular dynamics and PD, which will provide a more profound comprehension and put up with new therapeutic tactics for PD patients.

[Mechanism of heat-clearing prescriptions in alleviating type 2 diabetes mellitus:a review].

Type 2 diabetes mellitus(T2DM), a common chronic metabolic disease, is often accompanied by internal heat syndrome. Heat-clearing prescriptions are widely used to treat different heat syndromes of T2DM from the aspects of clearing stagnant heat, excess heat, damp heat, phlegm heat, and heat toxin, demonstrating remarkable effects. The mechanism of blood sugar-lowering agents has always been a hotspot of research. Recently, the basic studies of heat-clearing prescriptions from different perspectives have been increasing year by year. To clarify the mechanisms of heat-clearing prescriptions and find specific mechanisms, we systematically reviewed the basic studies of heat-clearing prescriptions commonly used for the treatment of T2DM in the past decade, intending to provide a reference for related research.

Alzheimer Disease and Epilepsy: A Mendelian Randomization Study.

BACKGROUND AND OBJECTIVES: Observational studies suggested a bidirectional relationship between Alzheimer disease (AD) and epilepsies. However, it remains debated whether and in which direction a causal association exists. This study aims to explore the relationship between genetic predisposition to AD, CSF biomarkers of AD (ß-amyloid [Aß] 42 and phosphorylated tau [pTau]), and epilepsies with 2-sample, bidirectional Mendelian randomization (MR) method. METHODS: Genetic instruments were obtained from large-scale genome-wide meta-analysis of AD (Ncase/proxy = 111,326, Ncontrol = 677,663), CSF biomarkers of AD (Aß42 and pTau, N = 13,116), and epilepsy (Ncase = 15,212, Ncontrol = 29,677) of European ancestry. Epilepsy phenotypes included all epilepsy, generalized epilepsy, focal epilepsy, childhood absence epilepsy, juvenile absence epilepsy, juvenile myoclonic epilepsy, generalized epilepsy with tonic-clonic seizures, focal epilepsy with hippocampal sclerosis (focal HS), and lesion-negative focal epilepsy. Main analyses were performed using generalized summary data-based MR. Sensitivity analyses included inverse variance weighted, MR pleiotropy residual sum and outlier, MR-Egger, weighted mode, and weighted median. RESULTS: For forward analysis, genetic predisposition to AD was associated with an increased risk of generalized epilepsy (odds ratio [OR] 1.053, 95% CI 1.002-1.105, p = 0.038) and focal HS (OR 1.013, 95% CI 1.004-1.022, p = 0.004). These associations were consistent across sensitivity analyses and replicated using a separate set of genetic instruments from another AD genome-wide association study. For reverse analysis, there was a suggestive effect of focal HS on AD (OR 3.994, 95% CI 1.172-13.613, p = 0.027). In addition, genetically predicted lower CSF Aß42 was associated with an increased risk of generalized epilepsy (ß = 0.090, 95% CI 0.022-0.158, p = 0.010). DISCUSSION: This MR study supports a causal link between AD, amyloid pathology, and generalized epilepsy. This study also indicates a close association between AD and focal HS. More effort should be made to screen seizure in AD, unravel its clinical implications, and explore its role as a putative modifiable risk factor.

The effects of AQP4 rs162009 on resting-state brain activity in Parkinson's disease.

BACKGROUND: We previously identified a significant association between Aquaporin-4 (AQP4) and Parkinson's disease (PD). OBJECTIVES: To identify whether AQP4 single-nucleotide polymorphism (SNP) rs162009 affects regional brain activity and clinical phenotypes of PD. METHODS: Low-frequency fluctuation amplitude (ALFF) was used to evaluate spontaneous brain activity, regional homogeneity (ReHo) was used to evaluate the pace of activity of adjacent voxel regions, and degree centrality (DC) was used to describe the functional connection strength between a voxel and the whole brain. Disease severity and PD stage were assessed with the Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale and Hoehn and Yahr scales, and the Montreal Cognitive Assessment (MoCA) was used to assess the participants' cognitive function. RESULTS: In patients with PD, AQP4 SNP rs162009 was associated with a significant higher ALFF in the right caudate head and the left occipital gyrus, a significant lower ReHo in the right inferior frontal gyrus, a different DC in the right frontal gyrus, the left calcarine, and the right inferior temporal gyrus. A significant positive correlation between ALFF in the right caudate head and MoCA in rs162009_A carriers was found. A significant negative correlation between the DC at the left calcarine and MDS-UPDRS and MDS-UPDRS III in rs162009_A noncarriers was found. CONCLUSIONS: Our study further revealed the effect of AQP4 SNP rs162009 on brain activity in PD, indicating that AQP4 may play an important role in PD neuropathophysiology.

Reduced coupling of global brain function and cerebrospinal fluid dynamics in Parkinson's disease.

Dysfunction of the glymphatic system, an intracranial clearance pathway that drains misfolded proteins, has been implicated in the onset of Parkinson's disease (PD). Recently, the coupling strength of global blood-oxygen-level-dependent (gBOLD) signals and cerebrospinal fluid (CSF) inflow dynamics have been suggested to be an indicator of glymphatic function. Using resting-state functional magnetic resonance imaging (MRI), we quantified gBOLD-CSF coupling strength as the cross-correlation between baseline gBOLD and CSF inflow signals to evaluate glymphatic function and its association with the clinical manifestations of PD. We found that gBOLD-CSF coupling in drug-naïve PD patients was significantly weaker than that in normal controls, but significantly stronger in patients less affected by sleep disturbances than in those more affected by sleep disturbances, based on the PD sleep scale. Furthermore, we collected longitudinal data from patients and found that baseline gBOLD-CSF coupling negatively correlated with the rate of change over time, but positively correlated with the rate of change in UPDRS-III scores. In conclusion, severe gBOLD-CSF decoupling in PD patients may reflect longitudinal motor impairment, thereby providing a potential marker of glymphatic dysfunction in PD.

Generation of a human iPSC line (CIBi013-A) from a patient with young-onset Parkinson's disease carrying a novel homozygous PARK7 (DJ-1) mutation.

Mutations in PARK7 and the resulting alterations in its production protein (DJ-1) are tightly associated with Parkinson's disease. We generated a human induced pluripotent stem cell (iPSC) line (CIBi013-A) from a patient with young-onset Parkinson's disease (YOPD) who carried a novel homozygous PARK7 (DJ-1) mutation (chr1:8037723, c.334C>G). The generated iPSCs will be used for investigating phenotype and underlying molecular mechanisms in patient-derived cells.

Generation of a human iPSC line (CIBi014-A) from a patient with Parkinson's disease carrying a novel heterozygotic PARK8 (LRRK2) mutation.

Leucine-rich repeat kinase 2 (LRRK2), also known as Dardarin (derived from the Basque word "dardara," meaning tremor), is a protein kinase encoded by the PARK8 gene. This protein is mainly distributed in the cytoplasm; however, it is also present in the mitochondrial outer membrane. Mutations in the LRRK2 protein cause Parkinson's disease (PD). We generated a human induced pluripotent stem cell (iPSC) line (CIBi014-A) expressing pluripotency markers. This cell line exhibited a normal karyotype and could be differentiated into three germ layers in vitro. This line will be valuable for investigating the mechanism underlying PD and identifying potential therapeutic targets.

Noninvasive neuroimaging provides evidence for deterioration of the glymphatic system in Parkinson's disease relative to essential tremor.

INTRODUCTION: Growing evidence has demonstrated dysfunction of the glymphatic system in α-synucleinopathy and related diseases. In this study, we aimed to use diffusion tensor image analysis along the perivascular space (DTI-ALPS) and MRI-visible enlarged perivascular spaces (EPVS) to evaluate glymphatic system function quantitatively and qualitatively and its relationship to clinical scores of disease severity in Parkinson's disease (PD) and essential tremor (ET). METHODS: Overall, 124 patients with PD, 74 with ET, and 106 healthy controls (HC) were enrolled. Two trained neurologists performed quantitative calculations of ALPS on DTI and visual ratings of EPVS on T2-weighted images in the centrum semiovale (CSO), basal ganglia (BG), midbrain, and cerebellum. RESULTS: The ALPS index was lower in patients with PD than in patients with ET (p < 0.001) and HC (p < 0.001). Similarly, patients with PD showed a more severe EPVS burden in the CSO, BG, and midbrain compared to ET and HC. Moreover, the ALPS index was negatively correlated with disease severity in the PD subgroups; however, it did not differ within the ET subgroup. No differences in ALPS or EPVS were observed between the ET and HC groups. CONCLUSION: In conclusion, DTI-ALPS and EPVS both provide neuroimaging evidence of glymphatic system dysfunction in PD, which further supports that PD is an α-synucleinopathy disease, while ET is a cerebellar dysfunction-related disease.

The regulatory roles of circular RNAs via autophagy in ischemic stroke.

Ischemic stroke (IS) is a severe disease with a high disability, recurrence, and mortality rates. Autophagy, a highly conserved process that degrades damaged or aging organelles and excess cellular components to maintain homeostasis, is activated during IS. It influences the blood-brain barrier integrity and regulates apoptosis. Circular RNAs (circRNAs) are novel non-coding RNAs involved in IS-induced autophagy and participate in various pathological processes following IS. In addition, they play a role in autophagy regulation. This review summarizes current evidence on the roles of autophagy and circRNA in IS and the potential mechanisms by which circRNAs regulate autophagy to influence IS injury. This review serves as a basis for the clinical application of circRNAs as novel biomarkers and therapeutic targets in the future.

Circular RNA hsa_circ_0003574 as a biomarker for prediction and diagnosis of ischemic stroke caused by intracranial atherosclerotic stenosis.

Background: Intracranial atherosclerotic stenosis (ICAS) is a common cause of first and recurrent ischemic stroke worldwide. Circular RNAs (circRNA)s have been recently suggested as candidate biomarkers in diagnosing and prognosis of ischemic stroke. A few circRNAs even serve as therapeutic targets that improves neurological function after ischemic stroke. However, the roles of circRNAs in ICAS caused ischemic stroke (ICAS-stroke) have not been fully understood. Therefore, in this study, we attempted to find some clues by investigating the different expression profiles of circRNAs between patients diagnosed with ICAS-stroke and normal control (NC)s. Methods: The OE Biotech Human ceRNA Microarray 4 × 180 K (47, 899 probes) screened circRNAs differentially expressed in peripheral blood in a discovery cohort (5 NCs versus five patients with ICAS-stroke). Afterwards, a validation cohort (31 NCs versus 48 patients with ICAS-stroke) was performed by quantitative polymerase chain reaction (qPCR). Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) and CircRNA-microRNA-mRNA interaction network was performed to identify potential interactions with microRNAs and pathway-deregulated circRNAs. Results: There were 244 circRNAs differentially expressed in patients diagnosed with ICAS-stroke compared with NCs [fold change (FC) ≥ 2.0 and p-value<0.05]. Among the 244 circRNAs, 5 circRNAs (hsa_circ_0003574, hsa_circ_0010509, hsa_circ_0026628, hsa_circ_0074057, hsa_circ_0016993) were selected for following verification by qPCR. Only hsa_circRNA_0003574 was significantly upregulated in patients than in NCs. GO analysis indicated that predicted target genes involved various biological processes, cellular components, and molecular functions. KEGG analysis showed that many genes were enriched within the arginine and proline metabolism, pyrimidine metabolism, arginine and proline metabolism, lysosome, cytokine-cytokine receptor interaction, and RNA transport. The circRNA-miRNA-mRNA network analysis show the miRNAs that has_circ_0003574 likely interacts with. Conclusion: We observed that hsa_circRNA_0003574 is upregulated in patients with ICAS-stroke compared with NCs, indicating it may be a potential novel biomarker and therapeutic target for ICAS-stroke. In addition, we analyzed the laboratory results and found that homocysteine and glycosylated hemoglobin were elevated among ICAS-stroke patients. The relationship between hsa_circRNA_0003574 and these parameters requires further investigation.

Different patterns of exosomal α-synuclein between Parkinson's disease and probable rapid eye movement sleep behavior disorder.

BACKGROUND AND PURPOSE: The insidious onset of Parkinson's disease (PD) makes early diagnosis difficult. Notably, idiopathic rapid eye movement sleep behavior disorder (iRBD) was reported as a prodrome of PD, which may represent a breakthrough for the early diagnosis of PD. However, currently there is no reliable biomarker for PD diagnosis. Considering that α-synuclein (α-Syn) and neuroinflammation are known to develop prior to the onset of clinical symptoms in PD, it was hypothesized that plasma total exosomal α-Syn (t-exo α-Syn), neural-derived exosomal α-Syn (n-exo α-Syn) and exosomal apoptosis-associated speck-like protein containing a caspase activation and recruitment domain (ASC) may be potential biomarkers of PD. METHODS: In this study, 78 PD patients, 153 probable iRBD patients (pRBD) and 63 healthy controls (HCs) were recruited. α-Syn concentrations were measured using a one-step paramagnetic particle-based chemiluminescence immunoassay, and ASC levels were measured using the Ella system. RESULTS: It was found that t-exo α-Syn was significantly increased in the PD group compared to the pRBD and HC groups (p < 0.0001), whilst n-exo α-Syn levels were significantly increased in both the PD and pRBD groups compared to HCs (p < 0.0001). Furthermore, although no difference was found in ASC levels between the PD and pRBD groups, there was a positive correlation between ASC and α-Syn in exosomes. CONCLUSIONS: Our results suggest that both t-exo α-Syn and n-exo α-Syn were elevated in the PD group, whilst only n-exo α-Syn was elevated in the pRBD group. Additionally, the adaptor protein of inflammasome ASC is correlated with α-Syn and may facilitate synucleinopathy.

Intratumoral IL-28B Gene Delivery Elicits Antitumor Effects by Remodeling of the Tumor Microenvironment in H22-Bearing Mice.

IL-28B, belonging to type III interferons (IFN-λs), exhibits a potent antitumor activity with reduced regulated T cells (Tregs) population, yet the effect of IL-28B on the tumor microenvironment (TME) and if IL-28B can downregulate Tregs directly in vitro are still unknown. In this study, we investigated the effects of IL-28B on Tregs in the spleen and TME in H22 tumor-bearing mice and verified the downregulation of IL-28B on Tregs in vitro. We found that rAd-mIL-28B significantly inhibited tumor growth and reduced the frequency of splenic CD4+Foxp3+ T cells. The levels of CXCL13, ICAM-1, MCP-5, and IL-7 in the serum, and the levels of IL-15 and sFasL in the tumor tissue decreased significantly after rAd-mIL-28B treatment relative to rAd-EGFP. Furthermore, the percentage of CD8+ cells in the TME was significantly increased in the rAd-mIL-28B group compared with the untreated group. In vitro, splenocytes were stimulated with anti-CD3/CD28 and IL-2 in the presence of TGF-ß with or without IL-28B for three days and followed by flow cytometric, RT-PCR, and IL-10 production analysis. The results showed that IL-28B significantly reduced the proportion of induced Foxp3+ cells. It demonstrated that IL-28B may be used as a promising immunotherapy strategy against cancer.

Potential Chemoprevention of Paeoniflorin in Colitis-Associated Colorectal Cancer by Network Pharmacology, Molecular Docking, and In Vivo Experiment.

Chronic inflammation plays a positive role in the development and progression of colitis-associated colorectal cancer (CAC). Medicinal plants and their extracts with anti-inflammatory and immunoregulatory properties may be an effective treatment and prevention strategy for CAC. This research aimed to explore the potential chemoprevention of paeoniflorin (PF) for CAC by network pharmacology, molecular docking technology, and in vivo experiments. The results showed that interleukin-6 (IL-6) is a key target of PF against CAC. In the CAC mouse model, PF increased the survival rate of mice and decreased the number and size of colon tumors. Moreover, reduced histological score of colitis and expression of Ki-67 and PCNA were observed in PF-treated mice. In addition, the chemoprevention mechanisms of PF in CAC may be associated with suppression of the IL-6/STAT3 signaling pathway and the IL-17 level. This research provides experimental evidence of potential chemoprevention strategies for CAC treatment.

Neuroimaging evidence of glymphatic system dysfunction in possible REM sleep behavior disorder and Parkinson's disease.

Alpha-synucleinopathy is postulated to be central to both idiopathic rapid eye movement sleep behaviour disorder (iRBD) and Parkinson's disease (PD). Growing evidence suggests an association between the diminished clearance of α-synuclein and glymphatic system dysfunction. However, evidence accumulating primarily based on clinical data to support glymphatic system dysfunction in patients with iRBD and PD is currently insufficient. This study aimed to use diffusion tensor image analysis along the perivascular space (DTI-ALPS) to evaluate glymphatic system activity and its relationship to clinical scores of disease severity in patients with possible iRBD (piRBDs) and those with PD. Further, we validated the correlation between the ALPS index and the prognosis of PD longitudinally. Overall, 168 patients with PD, 119 piRBDs, and 129 healthy controls were enroled. Among them, 50 patients with PD had been longitudinally reexamined. Patients with PD exhibited a lower ALPS index than those with piRBDs (P = 0.036), and both patient groups showed a lower ALPS index than healthy controls (P < 0.001 and P = 0.001). The ALPS index and elevated disease severity were negatively correlated in the piRBD and PD subgroups. Moreover, the ALPS index was correlated with cognitive decline in patients with PD in the longitudinal analyses. In conclusion, DTI-ALPS provided neuroimaging evidence of glymphatic system dysfunction in piRBDs and patients with PD; however, the potential of assessing the pathological progress of α-synucleinopathies as an indicator is worth verifying. Further development of imaging methods for glymphatic system function is also warranted.

Apolipoprotein E Genotype Contributes to Motor Progression in Parkinson's Disease.

BACKGROUND: Emerging evidence indicates that the apolipoprotein E (APOE) ε4 exacerbates α-synuclein pathology. OBJECTIVE: To determine whether APOE ε4 contributes to motor progression in early Parkinson's disease (PD). METHODS: Longitudinal data were obtained from 384 patients with PD divided into APOE ε4 carriers (n = 85) and noncarriers (n = 299) in the Parkinson's Progression Marker Initiative. Participants underwent yearly motor assessments over a mean follow-up period of 78.9 months. Repeated measures and linear mixed models were used to test the effects of APOE ε4. RESULTS: The motor progression was significantly more rapid in patients with PD carrying APOE ε4 than in noncarriers (ß = 0.283, P = 0.026, 95% confidence interval: 0.033-0.532). Through subgroup analysis, we found that the effect of APOE ε4 was significant only in patients with high amyloid ß burden (ß = 0.761, P < 0.001, 95% confidence interval: 0.0356-1.167). CONCLUSIONS: APOE ε4 may be associated with rapid motor progression in PD. © 2021 International Parkinson and Movement Disorder Society.

A new perspective on cerebrospinal fluid dynamics after subarachnoid hemorrhage: From normal physiology to pathophysiological changes.

Knowledge about the dynamic metabolism and function of cerebrospinal fluid (CSF) physiology has rapidly progressed in recent decades. It has traditionally been suggested that CSF is produced by the choroid plexus and drains to the arachnoid villi. However, recent findings have revealed that the brain parenchyma produces a large portion of CSF and drains through the perivascular glymphatic system and meningeal lymphatic vessels into the blood. The primary function of CSF is not limited to maintaining physiological CNS homeostasis but also participates in clearing waste products resulting from neurodegenerative diseases and acute brain injury. Aneurysmal subarachnoid hemorrhage (SAH), a disastrous subtype of acute brain injury, is associated with high mortality and morbidity. Post-SAH complications contribute to the poor outcomes associated with SAH. Recently, abnormal CSF flow was suggested to play an essential role in the post-SAH pathophysiological changes, such as increased intracerebral pressure, brain edema formation, hydrocephalus, and delayed blood clearance. An in-depth understanding of CSF dynamics in post-SAH events would shed light on potential development of SAH treatment options. This review summarizes and updates the latest physiological characteristics of CSF dynamics and discusses potential pathophysiological changes and therapeutic targets after SAH.

Opportunities and challenges of glioma organoids.

Glioma is the most common primary brain tumor and its prognosis is poor. Despite surgical removal, glioma is still prone to recurrence because it grows rapidly in the brain, is resistant to chemotherapy, and is highly aggressive. Therefore, there is an urgent need for a platform to study the cell dynamics of gliomas in order to discover the characteristics of the disease and develop more effective treatments. Although 2D cell models and animal models in previous studies have provided great help for our research, they also have many defects. Recently, scientific researchers have constructed a 3D structure called Organoids, which is similar to the structure of human tissues and organs. Organoids can perfectly compensate for the shortcomings of previous glioma models and are currently the most suitable research platform for glioma research. Therefore, we review the three methods currently used to establish glioma organoids. And introduced how they play a role in the diagnosis and treatment of glioma. Finally, we also summarized the current bottlenecks and difficulties encountered by glioma organoids, and the current efforts to solve these difficulties. Video Abstract.