α-Synuclein reduces acetylserotonin O-methyltransferase mediated melatonin biosynthesis by microtubule-associated protein 1 light chain 3 beta-related degradation pathway.

Previous studies have demonstrated that α-synuclein (α-SYN) is closely associated with rapid eye movement sleep behavior disorder (RBD) related to several neurodegenerative disorders. However, the exact molecular mechanisms are still rarely investigated. In the present study, we found that in the α-SYNA53T induced RBD-like behavior mouse model, the melatonin level in the plasma and pineal gland were significantly decreased. To elucidate the underlying mechanism of α-SYN-induced melatonin reduction, we investigated the effect of α-SYN in melatonin biosynthesis. Our findings showed that α-SYN reduced the level and activity of melatonin synthesis enzyme acetylserotonin O-methyltransferase (ASMT) in the pineal gland and in the cell cultures. In addition, we found that microtubule-associated protein 1 light chain 3 beta (LC3B) as an important autophagy adapter is involved in the degradation of ASMT. Immunoprecipitation assays revealed that α-SYN increases the binding between LC3B and ASMT, leading to ASMT degradation and a consequent reduction in melatonin biosynthesis. Collectively, our results demonstrate the molecular mechanisms of α-SYN in melatonin biosynthesis, indicating that melatonin is an important molecule involved in the α-SYN-associated RBD-like behaviors, which may provide a potential therapeutic target for RBD of Parkinson's disease.

The role of Nurr1-miR-30e-5p-NLRP3 axis in inflammation-mediated neurodegeneration: insights from mouse models and patients' studies in Parkinson's disease.

Nuclear receptor related-1 (Nurr1), a ligand-activated transcription factor, is considered a potential susceptibility gene for Parkinson's disease (PD), and has been demonstrated to possess protective effects against inflammation-induced neuronal damage. Despite the evidence showing decreased NURR1 level and increased pro-inflammatory cytokines in cell and animal models as well as in PD patients' peripheral blood mononuclear cells (PBMCs), the underlying mechanism remains elusive. In this study, we investigated the molecular mechanism of Nurr1 in PD-related inflammation. Through the miRNA-sequencing and verification in PBMCs from a cohort of 450 individuals, we identified a significant change of a Nurr1-dependent miRNA miR-30e-5p in PD patients compared to healthy controls (HC). Additionally, PD patients exhibited an elevated plasma interleukin-1ß (IL-1ß) level and increased nucleotide-binding domain-like receptor protein 3 (NLRP3) expression in PBMCs compared to HC. Statistical analyses revealed significant correlations among NURR1, miR-30e-5p, and NLRP3 levels in the PBMCs of PD patients. To further explore the involvement of Nurr1-miR-30e-5p-NLRP3 axis in the inflammation-mediated PD pathology, we developed a mouse model (Nurr1flox+/Cd11b-cre+, Nurr1cKO) conditionally knocking out Nurr1 in Cd11b-expressing cells. Our investigations in Nurr1cKO mice unveiled significant dopaminergic neurodegeneration following lipopolysaccharide-induced inflammation. Remarkably, Nurr1 deficiency triggered microglial activation and activated NLRP3 inflammasome, resulting in increased IL-1ß secretion. Coincidently, we found that miR-30e-5p level was significantly decreased in the PBMCs and primary microglia of Nurr1cKO mice compared to the controls. Furthermore, our in vitro experiments demonstrated that miR-30e-5p specifically targeted NLRP3. In Nurr1-knockdown microglia, NLRP3 expression was upregulated via miR-30e-5p. In summary, our findings highlight the involvement of Nurr1-miR-30e-5p-NLRP3 axis in the inflammation-mediated neurodegeneration in PD, the results of which may offer promising prospects for developing PD biomarkers and targeted therapeutic interventions.

Advances in NURR1-Regulated Neuroinflammation Associated with Parkinson's Disease.

Neuroinflammation plays a crucial role in the progression of neurodegenerative disorders, particularly Parkinson's disease (PD). Glial cell activation and subsequent adaptive immune involvement are neuroinflammatory features in familial and idiopathic PD, resulting in the death of dopaminergic neuron cells. An oxidative stress response, inflammatory mediator production, and immune cell recruitment and activation are all hallmarks of this activation, leading to chronic neuroinflammation and progressive neurodegeneration. Several studies in PD patients' cerebrospinal fluid and peripheral blood revealed alterations in inflammatory markers and immune cell populations that may lead to or exacerbate neuroinflammation and perpetuate the neurodegenerative process. Most of the genes causing PD are also expressed in astrocytes and microglia, converting their neuroprotective role into a pathogenic one and contributing to disease onset and progression. Nuclear receptor-related transcription factor 1 (NURR1) regulates gene expression linked to dopaminergic neuron genesis and functional maintenance. In addition to playing a key role in developing and maintaining neurotransmitter phenotypes in dopaminergic neurons, NURR1 agonists have been shown to reverse behavioral and histological abnormalities in animal PD models. NURR1 protects dopaminergic neurons from inflammation-induced degeneration, specifically attenuating neuronal death by suppressing the expression of inflammatory genes in microglia and astrocytes. This narrative review highlights the inflammatory changes in PD and the advances in NURR1-regulated neuroinflammation associated with PD. Further, we present new evidence that targeting this inflammation with a variety of potential NURR1 target therapy medications can effectively slow the progression of chronic neuroinflammation-induced PD.

Tetrahedral DNA nanostructures functionalized by multivalent microRNA132 antisense oligonucleotides promote the differentiation of mouse embryonic stem cells into dopaminergic neurons.

MicroRNA132 (miR132) negatively regulates the differentiation of mouse embryonic stem cells (ESCs) into dopaminergic (DAergic) neurons; in contrast, antisense oligonucleotide against miR132 (miR132-ASO) effectively blocks the activity of endogenous miR132 and thereafter promotes the differentiation of DAergic neurons. However, it is difficult for miR132-ASO to enter cells without a suitable delivery system. Tetrahedral DNA nanostructures (TDNs), as a new type of DNA-based nanocarrier, have great potential in biomedical applications and even have been reported to promote stem cell differentiation. In this study, we developed functional multivalent DNA nanostructures by appending miR132-ASO motifs to three-dimensional TDNs (miR132-ASO-TDNs). Our data clearly revealed that miR132-ASO-TDNs exposure can promote the differentiation of ESCs into DAergic neurons as well as elevate DA release from differentiated DAergic neurons. MiR132-ASO-TDNs could serve as a novel biofunctional nanomaterial to improve the efficiency of DAergic neurons differentiation. Our findings may also provide a new approach for stem cell therapy against neurodegenerative diseases.

Cerebellar involvement in Parkinson's disease: Pathophysiology and neuroimaging.

ABSTRACT: Parkinson's disease (PD) is a neurodegenerative disease characterized by various motor and non-motor symptoms. The complexity of its symptoms suggests that PD is a heterogeneous neurological disorder. Its pathological changes are not limited to the substantia nigra-striatal system, but gradually extending to other regions including the cerebellum. The cerebellum is connected to a wide range of central nervous system regions that form essential neural circuits affected by PD. In addition, altered dopaminergic activity and α-synuclein pathology are found in the cerebellum, further suggesting its role in the PD progression. Furthermore, an increasing evidence obtained from imaging studies has demonstrated that cerebellar structure, functional connectivity, and neural metabolism are altered in PD when compared to healthy controls, as well as among different PD subtypes. This review provides a comprehensive summary of the cerebellar pathophysiology and results from neuroimaging studies related to both motor and non-motor symptoms of PD, highlighting the potential significance of cerebellar assessment in PD diagnosis, differential diagnosis, and disease monitoring.

A more objective PD diagnostic model: integrating texture feature markers of cerebellar gray matter and white matter through machine learning.

Objective: The purpose of this study is to explore whether machine learning can be used to establish an effective model for the diagnosis of Parkinson's disease (PD) by using texture features extracted from cerebellar gray matter and white matter, so as to identify subtle changes that cannot be observed by the naked eye. Method: This study involved a data collection period from June 2010 to March 2023, including 374 subjects from two cohorts. The Parkinson's Progression Markers Initiative (PPMI) served as the training set, with control group and PD patients (HC: 102 and PD: 102) from 24 global sites. Our institution's data was utilized as the test set (HC: 91 and PD: 79). Machine learning was employed to establish multiple models for PD diagnosis based on texture features of the cerebellum's gray and white matter. Results underwent evaluation through 5-fold cross-validation analysis, calculating the area under the receiver operating characteristic curve (AUC) for each model. The performance of each model was compared using the Delong test, and the interpretability of the optimized model was further augmented by employing Shapley additive explanations (SHAP). Results: The AUCs for all pipelines in the validation dataset were compared using FeAture Explorer (FAE) software. Among the models established by Kruskal-Wallis (KW) and logistic regression via Lasso (LRLasso), the AUC was highest using the "one-standard error" rule. 'WM_original_glrlm_GrayLevelNonUniformity' was considered the most stable and predictive feature. Conclusion: The texture features of cerebellar gray matter and white matter combined with machine learning may have potential value in the diagnosis of Parkinson's disease, in which the heterogeneity of white matter may be a more valuable imaging marker.

Linking the cerebellum to Parkinson disease: an update.

Parkinson disease (PD) is characterized by heterogeneous motor and non-motor symptoms, resulting from neurodegeneration involving various parts of the central nervous system. Although PD pathology predominantly involves the nigral-striatal system, growing evidence suggests that pathological changes extend beyond the basal ganglia into other parts of the brain, including the cerebellum. In addition to a primary involvement in motor control, the cerebellum is now known to also have an important role in cognitive, sleep and affective processes. Over the past decade, an accumulating body of research has provided clinical, pathological, neurophysiological, structural and functional neuroimaging findings that clearly establish a link between the cerebellum and PD. This Review presents an overview and update on the involvement of the cerebellum in the clinical features and pathogenesis of PD, which could provide a novel framework for a better understanding the heterogeneity of the disease.

Abnormal Vacuole Membrane Protein-1 Expression in Parkinson's Disease Patients.

Background: Parkinson's disease (PD) is pathologically characterized by progressive dopaminergic (DAergic) neuron loss in the substantia nigra pars compacta (SNpc) and accumulation of intracytoplasmic α-synuclein-containing Lewy bodies. Autophagy has been identified as a critical component in the development and progression of PD. Several autophagy genes have been identified as being altered in PD. One of those genes, vacuole membrane protein-1 (VMP1), an autophagy protein localized in the endoplasmic reticulum (ER) in DAergic neurons, has been shown to cause motor disorder, severe loss of DAergic neurons, and autophagy flux disturbance in the VMP1 knockout mouse model. Objective: To evaluate for the first time the alteration on the expression of the VMP1 gene and its clinical correlations in peripheral blood mononuclear cells (PBMCs) of a relatively large sample of PD patients. Methods: We assessed the VMP1 mRNA levels in PD patients (n = 229) and healthy controls (HC) (n = 209) using real-time quantitative PCR (RT-qPCR), and the VMP1 protein levels in PD patients (n = 27) and HC (n = 27) using Western blot (WB). Then, we analyzed the VMP1 expression levels and clinical features of PD patients. Results: Our findings revealed that VMP1 levels in the PD group were significantly lower than in the HC group (RT-qPCR p < 0.01 and WB p < 0.001). The VMP1 expression was significantly lower as the disease progressed, which could be ameliorated by administering DAergic receptor agonists. Moreover, receiver operating characteristic (ROC) curve analysis showed that VMP1 mRNA and protein level area under the curves (AUCs) were 64.5%, p < 0.01, and 83.4%, p < 0.01, respectively. Conclusion: This case-control study demonstrates that peripheral VMP1 level altered in PD patients and may serve as a potential endogenous diagnostic marker of PD.

Risk of ischemic stroke in patients with COVID-19 infection: A systematic review and meta-analysis.

An ongoing global pandemic, the coronavirus disease 2019 is posing threat to people all over the world. The association between COVID-19 and the risk of ischemic stroke remains unclear. This study systematically reviewed published studies and conducted meta-analysis to evaluate the association between the risk of ischemic stroke and COVID-19. This study was conducted according to guidelines from the Preferred Reporting Items for Systematic Reviews and Meta-Analyses. The protocol used in this study had been registered in the International Prospective Register of Systematic Reviews. EMBASE, PubMed, Cochrane Library and Web of Science were searched from 1st December 2019-19th February 2021. This systematic review and meta-analysis analysed the combined effect estimations based on odds ratios (OR) with the random-effects model. Four studies were screened from 31,634 participants including 171 COVID-19 positive patients with ischemic stroke were included. The mean age of COVID-19 positive patients with ischemic stroke was 69.45 years (Range: 63-77 years) and the male patients were 56%. Countries covered by these articles were USA, Italy and France. Three of the articles were retrospective cohort studies and one was prospective cohort study. Our analysis revealed that the risk of ischemic stroke (combined OR: 2.41; 95% CI: 1.08-5.38) was significantly increased. Four included studies were significantly heterogeneous (I2 = 75.2%, P = 0.007). Significant association between the risk of ischemic stroke and COVID-19 was observed in the North America group (combined OR: 2.90; 95% CI: 0.45-18.80, I2 = 89.60%, P = 0.002). This study found that the risk for ischemic stroke was increased in COVID-19 patients, especially in patients from North America. Further studies with larger sample sizes that include different ethnic populations are required to confirm our analysis.

Hot Topics in Recent Parkinson's Disease Research: Where We are and Where We Should Go.

Parkinson's disease (PD), the second most common neurodegenerative disease, is clinically characterized by both motor and non-motor symptoms. Although overall great achievements have been made in elucidating the etiology and pathogenesis of PD, the exact mechanisms of this complicated systemic disease are still far from being clearly understood. Consequently, most of the currently-used diagnostic tools and therapeutic options for PD are symptomatic. In this perspective review, we highlight the hot topics in recent PD research for both clinicians and researchers. Some of these hot topics, such as sleep disorders and gut symptoms, have been neglected but are currently emphasized due to their close association with PD. Following these research directions in future PD research may help understand the nature of the disease and facilitate the discovery of new strategies for the diagnosis and therapy of PD.

Role of Glia-Derived Extracellular Vesicles in Neurodegenerative Diseases.

Extracellular vesicles (EVs), as nano-sized vesicles secreted by almost all cells, have been recognized as the essential transmitter for cell-to-cell communication and participating in multiple biological processes. Neurodegenerative diseases (ND), such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis, share common mechanisms of the aggregation and propagation of distinct pathologic proteins among cells in the nervous systems and neuroinflammatory reactions mediated by glia during the pathogenic process. This feature indicates the vital role of crosstalk between neurons and glia in the pathogenesis of ND. In recent years, glia-derived EVs have been investigated as potential mediators of signals between neurons and glia, which provides a new direction and strategy for understanding ND. By a comprehensive summary, it can be concluded that glia-derived EVs have both a beneficial and/or a detrimental effect in the process of ND. Therefore, this review article conveys the role of glia-derived EVs in the pathogenesis of ND and raises current limitations of their potential application in the diagnosis and treatment of ND.

Comprehensive metabolic profiling of Parkinson's disease by liquid chromatography-mass spectrometry.

BACKGROUND: Parkinson's disease (PD) is a prevalent neurological disease in the elderly with increasing morbidity and mortality. Despite enormous efforts, rapid and accurate diagnosis of PD is still compromised. Metabolomics defines the final readout of genome-environment interactions through the analysis of the entire metabolic profile in biological matrices. Recently, unbiased metabolic profiling of human sample has been initiated to identify novel PD metabolic biomarkers and dysfunctional metabolic pathways, however, it remains a challenge to define reliable biomarker(s) for clinical use. METHODS: We presented a comprehensive metabolic evaluation for identifying crucial metabolic disturbances in PD using liquid chromatography-high resolution mass spectrometry-based metabolomics approach. Plasma samples from 3 independent cohorts (n = 460, 223 PD, 169 healthy controls (HCs) and 68 PD-unrelated neurological disease controls) were collected for the characterization of metabolic changes resulted from PD, antiparkinsonian treatment and potential interferences of other diseases. Unbiased multivariate and univariate analyses were performed to determine the most promising metabolic signatures from all metabolomic datasets. Multiple linear regressions were applied to investigate the associations of metabolites with age, duration time and stage of PD. The combinational biomarker model established by binary logistic regression analysis was validated by 3 cohorts. RESULTS: A list of metabolites including amino acids, acylcarnitines, organic acids, steroids, amides, and lipids from human plasma of 3 cohorts were identified. Compared with HC, we observed significant reductions of fatty acids (FFAs) and caffeine metabolites, elevations of bile acids and microbiota-derived deleterious metabolites, and alterations in steroid hormones in drug-naïve PD. Additionally, we found that L-dopa treatment could affect plasma metabolome involved in phenylalanine and tyrosine metabolism and alleviate the elevations of bile acids in PD. Finally, a metabolite panel of 4 biomarker candidates, including FFA 10:0, FFA 12:0, indolelactic acid and phenylacetyl-glutamine was identified based on comprehensive discovery and validation workflow. This panel showed favorable discriminating power for PD. CONCLUSIONS: This study may help improve our understanding of PD etiopathogenesis and facilitate target screening for therapeutic intervention. The metabolite panel identified in this study may provide novel approach for the clinical diagnosis of PD in the future.

α-Synuclein Up-regulates Monoamine Oxidase A Expression and Activity via Trans-Acting Transcription Factor 1.

Abnormal α-Synuclein (α-SYN) aggregates are the pathological hallmarks of Parkinson's disease (PD), which may affect dopamine (DA) neuron function and DA metabolism. Monoamine oxidase A (MAOA) is an enzyme located on the outer mitochondrial membrane that catalyzes the oxidative deamination of DA. Both α-SYN and MAOA are associated with PD pathogenesis, suggesting possible crosstalk between these two molecules. In the present study, we aimed to investigate the potential impacts of α-SYN on MAOA function and further explore the underlying mechanisms. Our study showed that overexpression of α-SYN [both wild-type (WT) and A53T] increased MAOA function via upregulating its expression without impacting MAOA stability. Overexpression of α-SYNWT or α-SYNA53T enhanced the transcription activity of the MAOA promoter region containing the binding sites of cell division cycle associated 7 like (R1, a transcriptional repressor of MAOA) and trans-acting transcription factor 1 (Sp1, a transcription factor of MAOA). Interestingly, α-SYN selectively increased Sp1 expression, thereby enhancing the binding capacity of Sp1 with MAOA promoter to increase MAOA expression. Taken together, our findings demonstrate that α-SYN can upregulate MAOA expression via modulation of Sp1 and may shed light on future studies of α-SYN associated PD pathogenesis.

Peripheral Clock System Abnormalities in Patients With Parkinson's Disease.

Objective: To evaluate the altered expression of peripheral clock genes, circulating melatonin levels, and their correlations with sleep-wake phenotypes including probable rapid eye movement sleep behavior disorder (pRBD) symptoms in a relatively large population of Parkinson's disease (PD) patients. Methods: We determined the expression profiles of five principal clock genes, BMAL1, CLOCK, CRY1, PER1, and PER2, in the peripheral blood mononuclear cells (PBMCs) of PD patients (n = 326), and healthy controls (HC, n = 314) using quantitative real-time PCR. Melatonin concentration in the plasma of two groups was evaluated by enzyme-linked immunosorbent assay. Then we performed comprehensive association analyses on the PBMCs clock gene expression, plasma melatonin levels and sleep characteristics. Results: Our data showed that the expression levels of BMAL1, CLOCK, CRY1, PER1, and PER2 were significantly decreased in the PBMCs of PD as compared with that of HC (P < 0.05). PD patients had reduced plasma melatonin levels compared with HC (P < 0.0001). pRBD and excessive daytime sleepiness are common in these PD patients and are associated with the expression levels of all five clock genes (r = -0.344∼-0.789, P < 0.01) and melatonin concentration (r = -0.509∼-0.753, P < 0.01). Statistical analyses also revealed that a combination of five clock genes and melatonin could reach a high diagnostic performance (areas under the curves, 97%) for PD comorbid pRBD. Conclusion: This case-control study demonstrates that peripheral BMAL1, CLOCK, CRY1, PER1, PER2, and melatonin levels are altered in PD patients and may serve as endogenous markers for sleep and wakefulness disturbances of PD.

Biomarkers for Parkinson's Disease: How Good Are They?

Parkinson's disease (PD) is a complex neurodegenerative disorder with no cure in sight. Clinical challenges of the disease include the inability to make a definitive diagnosis at the early stages and difficulties in predicting the disease progression. The unmet demand to identify reliable biomarkers for early diagnosis and management of the disease course of PD has attracted a lot of attention. However, only a few reported candidate biomarkers have been tried in clinical practice at the present time. Studies on PD biomarkers have often overemphasized the discovery of novel identity, whereas efforts to further evaluate such candidates are rare. Therefore, we update the new development of biomarker discovery in PD and discuss the standard process in the evaluation and assessment of the diagnostic or prognostic value of the identified potential PD biomarkers in this review article. Recent developments in combined biomarkers and the current status of clinical trials of biomarkers as outcome measures are also discussed. We believe that the combination of different biomarkers might enhance the specificity and sensitivity over a single measure that might not be sufficient for such a multiplex disease.

Whole exome sequencing identified a new compound heterozygous PRKN mutation in a Chinese family with early-onset Parkinson's disease.

Early-onset Parkinson's disease (EOPD) is usually caused by genetic variants and patients with EOPD develop symptoms before the age of 50, accounting for 5% Parkinson's disease (PD). Here we present a Chinese Han pedigree with clinical features of EOPD. To determine the diagnosis and pathogenic mutations of this pedigree, whole exome sequencing, Sanger sequencing and real-time quantitative PCR were performed to detect all the four family members. Our results showed that a new form of compound heterozygous mutation in the PRKN gene, consisting of heterozygous point mutation c.850G > C (p.G284R) along with exon 4 deletion, is the causative genetic factor for EOPD in this pedigree. These discoveries may have implications for genetic counseling, clinical management and developing PRKN target gene therapy strategy.

Piperine regulates glycogen synthase kinase-3ß-related signaling and attenuates cognitive decline in D-galactose-induced aging mouse model.

Aging-related cholinergic dysfunction, extensive neuroinflammation and oxidative stress in brain are predominant pathogenic factors for dementia. In the present study, we aimed to evaluate the protective effects of piperine, an alkaloid nutrient component of Piper nigrum, against cognitive impairment in a senescent mouse model induced by D-galactose (D-Gal) and to explore the underlying mechanisms. Senescent mouse model was established by repeated subcutaneous injection of D-Gal (150 mg/kg, once daily for 42 days). Fourteen days after the first D-Gal exposure, piperine (2.5, 5, 10 mg/kg) or vehicle was intraperitoneally administered once daily for 28 days. The cognitive function of mice was evaluated by Morris water maze test (MWM). Twenty-four hours after behavioral test, the cholinergic function and oxidative stress level in mouse hippocampus were measured by spectrophotometric assays. In addition, the hippocampal levels of proinflammatory cytokines, including tumor necrosis factor-α, interleukin-1ß and interleukin-6, were quantified using enzyme-linked immunosorbent assay. Expressions of glycogen synthase kinase-3ß (GSK-3ß) and its upstream or downstream molecules including phosphatidylinositol 3-kinase (PI3K)，protein kinase B (AKT), protein kinase C (PKC), NF-E2-related factor 2, nuclear factor-κB and microtubule-associated protein tau in hippocampus were determined by western blotting, immunohistochemical or immunofluorescent staining. Our data revealed that chronic D-Gal exposure in mice led to cognitive impairment in MWM, along with cholinergic malfunction, extensive oxidative stress and neuroinflammation, as well as hyperphosphorylation of tau protein in hippocampus. All these neurochemical, neuroinflammatory and cognitive alterations could be ameliorated by 4-week repeated piperine administration. Moreover, piperine also reversed D-Gal-induced GSK-3ß activation through modulating PKC and PI3K/AKT pathways in senescent mouse hippocampus, suggesting GSK-3ß-related signaling might be involved in the benefits of piperine against D-Gal-induced cognitive decline in mice.

Alteration of Metabolic Profile and Potential Biomarkers in the Plasma of Alzheimer's Disease.

The expending of elderly population worldwide has resulted in a dramatic rise in the incidence of chronic diseases such as Alzheimer's disease (AD). Inadequate understanding of the mechanisms underlying AD has hampered the development of efficient tools for definitive diagnosis and curative interventions. Previous studies have attempted to discover reliable biomarkers of AD, but these biomarkers can only be measured through invasive (neuropathological markers in cerebrospinal fluid) or expensive (positron emission tomography scanning or magnetic resonance imaging) techniques. Metabolomics is a high-throughput technology that can detect and catalog large numbers of small metabolites and may be a useful tool for characterization of AD and identification of biomarkers. In this study, we used ultra-performance liquid chromatography-mass spectrometry based untargeted metabolomics to measure the concentrations of plasma metabolites in a cohort of subjects with AD (n=44) and cognitively normal controls (Ctrl, n=94). The AD group showed marked reductions in levels of polyunsaturated fatty acids, acyl-carnitines, degradation products of tryptophan, and elevated levels of bile acids compared to the Ctrl group. We then validated the results using an independent cohort that included subjects with AD (n=30), mild cognitive impairment (MCI, n=13), healthy controls (n=43), and non-AD neurological disease controls (NDC, n=31). We identified five metabolites comprising cholic acid, chenodeoxycholic acid, allocholic acid, indolelactic acid, and tryptophan that were able to distinguish patients with AD from both Ctrl and NDC with satisfactory sensitivity and specificity. The concentrations of these metabolites were significantly correlated with disease severity. Our results also suggested that altered bile acid profiles in AD and MCI might indicate early risk for the development of AD. These findings may allow for development of new approaches for diagnosis of AD and may provide novel insights into AD pathogenesis.

Elevated Plasma microRNA-105-5p Level in Patients With Idiopathic Parkinson's Disease: A Potential Disease Biomarker.

Parkinson's disease (PD) is the second most common neurodegenerative disease, which still lacks a biomarker to aid in diagnosis and to differentiate diagnosis at the early stage of the disease. microRNAs (miRNAs) are small and evolutionary conserved non-coding RNAs that are involved in post-transcriptional gene regulation. Several miRNAs have been proposed as potential biomarkers in several diseases. In the present study, we screened miRNAs using a network vulnerability analysis, to evaluate their potential as PD biomarkers. We first extracted miRNAs that were differentially expressed between PD and healthy controls (HC) samples. Then we constructed the PD-specific miRNA-mRNA network and screened miRNA biomarkers using a new bioinformatics model. With this model, we identified miR-105-5p as a putative biomarker for PD. Moreover, we measured miR-105-5p levels in the plasma of patients with idiopathic PD (IPD) (n = 319), neurological disease controls (NDC, n = 305) and HC (n = 273) using reverse transcription real-time quantitative PCR (RT-qPCR). Our data clearly demonstrated that the plasma miR-105-5p level in IPD patients was significantly higher than those of HC (251%, p < 0.001) and NDC (347%, p < 0.001). There was no significant difference in miR-105-5p expression between IPD patients with or without anti-PD medications. Interestingly, we found that the plasma miR-105-5p expression level may be able to differentiate IPD from parkinsonian syndrome, essential tremor and other neurodegenerative diseases. We believe that a change in the plasma miR-105-5p level is a potential biomarker for IPD.

Piperine attenuates cognitive impairment in an experimental mouse model of sporadic Alzheimer's disease.

Piperine, the major alkaloid constituent of black pepper, has been reported to possess a wide range of pharmacological effects on the central nervous system, including antidepressant, anticonvulsant and anti-ischemic activities. In the present study, we aimed to investigate the therapeutic potential and neuroprotective mechanisms of piperine in an experimental mouse model of sporadic Alzheimer's disease (sAD) induced by intracerebroventricular (ICV) infusion of streptozotocin (STZ). STZ was infused bilaterally at a dose of 1.5 mg/kg/day on day 1 and day 3. From day 8, piperine (2.5-10 mg/kg body weight) was administered intraperitoneally once daily for 15 consecutive days. The locomotor activity and cognitive performance of mice were evaluated using open field test and Morris water maze test, respectively. On day 23, all animals were sacrificed, and the hippocampus was used for biochemical, neurochemical and neuroinflammatory determinations. Our data revealed that the ICV-STZ-infused sAD mouse showed an increased oxidative-nitrosative stress, an altered neurotransmission and an elevated neuroinflammation in hippocampus, as well as significant cognitive deficits. All these alterations can be ameliorated by piperine in a dose-dependent manner. In summary, our findings predict a therapeutic potential of piperine against cognitive deficits in sAD mouse. This effect might be due to its abilities to ameliorate oxidative-nitrosative stress, restore neurotransmission and reduce neuroinflammation.