Pyroptosis-mediator GSDMD promotes Parkinson's disease pathology via microglial activation and dopaminergic neuronal death.

GSDMD-mediated pyroptosis occurs in the nigrostriatal pathway in Parkinson's disease animals, yet the role of GSDMD in neuroinflammation and death of dopaminergic neurons in Parkinson's disease remains elusive. Here, our in vivo and in vitro studies demonstrated that GSDMD, as a pyroptosis executor, contributed to glial reaction and death of dopaminergic neurons across different Parkinson's disease models. The ablation of the Gsdmd attenuated Parkinson's disease damage by reducing dopaminergic neuronal death, microglial activation, and detrimental transformation. Disulfiram, an inhibitor blocking GSDMD pore formation, efficiently curtailed pyroptosis, thereby lessening the pathology of Parkinson's disease. Additionally, a modification in GSDMD was identified in the blood of Parkinson's disease patients in contrast to healthy subjects. Therefore, the detected alteration in GSDMD within the blood of Parkinson's disease patients and the protective impact of disulfiram could be promising for the diagnostic and therapeutic approaches against Parkinson's disease.

Hypoxia inducible factor-1α regulates microglial innate immune memory and the pathology of Parkinson's disease.

Neuroinflammation is one of the core pathological features of Parkinson's disease (PD). Innate immune cells play a crucial role in the progression of PD. Microglia, the major innate immune cells in the brain, exhibit innate immune memory effects and are recognized as key regulators of neuroinflammatory responses. Persistent modifications of microglia provoked by the first stimuli are pivotal for innate immune memory, resulting in an enhanced or suppressed immune response to second stimuli, which is known as innate immune training and innate immune tolerance, respectively. In this study, LPS was used to establish in vitro and in vivo models of innate immune memory. Microglia-specific Hif-1α knockout mice were further employed to elucidate the regulatory role of HIF-1α in innate immune memory and MPTP-induced PD pathology. Our results showed that different paradigms of LPS could induce innate immune training or tolerance in the nigrostriatal pathway of mice. We found that innate immune tolerance lasting for one month protected the dopaminergic system in PD mice, whereas the effect of innate immune training was limited. Deficiency of HIF-1α in microglia impeded the formation of innate immune memory and exerted protective effects in MPTP-intoxicated mice by suppressing neuroinflammation. Therefore, HIF-1α is essential for microglial innate immune memory and can promote neuroinflammation associated with PD.

The causal relationship between 25-hydroxyvitamin D and serum lipids levels: A bidirectional two-sample mendelian randomization study.

Serum vitamin D levels were linked to lipid metabolism in observational studies, but the exact mechanism was unclear. Several studies have attempted to decipher the relationship between 25(OH)D and lipid levels. Conventional observational studies are vulnerable to confounding. Mendelian randomization (MR) analysis can better control for confounding factors and reverse causality, allowing for the inference of causal association. We, therefore, sought to use MR to investigate the possible causal relationship between 25(OH)D and blood lipid levels (HDL cholesterol, LDL cholesterol, triglycerides, and total cholesterol). A bidirectional two-sample Mendelian randomization (MR) was performed on data primarily from European ancestors. In addition, the potential causal effect of lipids on 25(OH)D was assessed by regressor-based multivariate magnetic resonance (MVMR). The single-nucleotide polymorphisms (SNPs) related to 25(OH)D were selected from a large-scale genome-wide association study (GWAS) database named IEU GWAS, and the SNPs associated with the four blood lipids were chosen from UK Biobank (UKB) lipid GWAS. When blood lipids were the outcome, the results of bidirectional two-sample MR demonstrated that 25(OH)D exhibited a negative causal association with TG, TC, and LDL-C: ß = - 0.23, 95% CI = -0.28 to -0.19, P<0.001; ß = - 0.16, 95% CI: - 0.30 to-0.03, P < 0.05; ß = - 0.11, 95% CI: - 0.23 to 0, P < 0.05. There was no causal relationship between 25(OH)D and HDL-C (ß = 0.05, 95% CI: - 0.11 to 0.20, P = 0.56). When setting blood lipids as exposure, TG and 25(OH)D, ß = -0.13, 95% CI: - 0.15 to -0.10, P < 0.05; TC and 25(OH)D, ß = -0.11, 95% CI: - 0.15 to -0.07, P < 0.05; HDL-C and 25(OH)D, ß = 0.02, 95% CI: 0 to 0.03, P = 0.07; LDL-C and 25(OH)D, ß = -0.08, 95% CI: - 0.11 to -0.05, P < 0.05). Our MVMR study also showed a significant relationship between genetically determined lipid traits and 25(OH)D levels (TG and 25(OH)D, P < 0.05; TC and 25(OH)D, P < 0.05). In all MR analyses, there was no horizontal pleiotropy (all P > 0.05), or statistical heterogeneity. The "Leave-one-out" sensitivity analysis confirmed the stability of our results. MR Studies have shown a bidirectional causal relationship between genetically-determined 25(OH)D levels and serum TG and TC levels. The findings have potential implications for etiological understanding and disease prevention.

Metabolism-related brain morphology accelerates aging and predicts neurodegenerative diseases and stroke: a UK Biobank study.

Metabolic syndrome (MetS) is characterized by a constellation of metabolic risk factors, including obesity, hypertriglyceridemia, low high-density lipoprotein (HDL) levels, hypertension, and hyperglycemia, and is associated with stroke and neurodegenerative diseases. This study capitalized on brain structural images and clinical data from the UK Biobank and explored the associations of brain morphology with MetS and brain aging due to MetS. Cortical surface area, thickness, and subcortical volumes were assessed using FreeSurfer. Linear regression was used to examine associations of brain morphology with five MetS components and the MetS severity in a metabolic aging group (N = 23,676, age 62.8 ± 7.5 years). Partial least squares (PLS) were employed to predict brain age using MetS-associated brain morphology. The five MetS components and MetS severity were associated with increased cortical surface area and decreased thickness, particularly in the frontal, temporal, and sensorimotor cortex, and reduced volumes in the basal ganglia. Obesity best explained the variation of brain morphology. Moreover, participants with the most severe MetS had brain age 1-year older than those without MetS. Brain age in patients with stroke (N = 1042), dementia (N = 83), Parkinson's (N = 107), and multiple sclerosis (N = 235) was greater than that in the metabolic aging group. The obesity-related brain morphology had the leading discriminative power. Therefore, the MetS-related brain morphological model can be used for risk assessment of stroke and neurodegenerative diseases. Our findings suggested that prioritizing adjusting obesity among the five metabolic components may be more helpful for improving brain health in aging populations.

Amyloid-ß accumulation in relation to functional connectivity in aging: A longitudinal study.

The brain undergoes many changes at pathological and functional levels in healthy aging. This study employed a longitudinal and multimodal imaging dataset from the OASIS-3 study (n = 300) and explored possible relationships between amyloid beta (Aß) accumulation and functional brain organization over time in healthy aging. We used positron emission tomography (PET) with Pittsburgh compound-B (PIB) to quantify the Aß accumulation in the brain and resting-state functional MRI (rs-fMRI) to measure functional connectivity (FC) among brain regions. Each participant had at least 2 to 3 follow-up visits. A linear mixed-effect model was used to examine longitudinal changes of Aß accumulation and FC throughout the whole brain. We found that the limbic and frontoparietal networks had a greater annual Aß accumulation and a slower decline in FC in aging. Additionally, the amount of the Aß deposition in the amygdala network at baseline slowed down the decline in its FC in aging. Furthermore, the functional connectivity of the limbic, default mode network (DMN), and frontoparietal networks accelerated the Aß propagation across their functionally highly connected regions. The functional connectivity of the somatomotor and visual networks accelerated the Aß propagation across the brain regions in the limbic, frontoparietal, and DMN networks. These findings suggested that the slower decline in the functional connectivity of the functional hubs may compensate for their greater Aß accumulation in aging. The Aß propagation from one brain region to the other may depend on their functional connectivity strength.

NOD-like receptor NLRC5 promotes neuroinflammation and inhibits neuronal survival in Parkinson's disease models.

Parkinson's disease (PD) is mainly characterized by the progressive degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and neuroinflammation mediated by overactivated microglia and astrocytes. NLRC5 (nucleotide-binding oligomerization domain-like receptor family caspase recruitment domain containing 5) has been reported to participate in various immune disorders, but its role in neurodegenerative diseases remains unclear. In the current study, we found that the expression of NLRC5 was increased in the nigrostriatal axis of mice with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (MPTP)-induced PD, as well as in primary astrocytes, microglia and neurons exposed to different neurotoxic stimuli. In an acute MPTP-induced PD model, NLRC5 deficiency significantly reduced dopaminergic system degeneration and ameliorated motor deficits and striatal inflammation. Furthermore, we found that NLRC5 deficiency decreased the expression of the proinflammatory genes IL-1ß, IL-6, TNF-α and COX2 in primary microglia and primary astrocytes treated with neuroinflammatory stimuli and reduced the inflammatory response in mixed glial cells in response to LPS treatment. Moreover, NLRC5 deficiency suppressed activation of the NF-κB and MAPK signaling pathways and enhanced the activation of AKT-GSK-3ß and AMPK signaling in mixed glial cells. Furthermore, NLRC5 deficiency increased the survival of primary neurons treated with MPP+ or conditioned medium from LPS-stimulated mixed glial cells and promoted activation of the NF-κB and AKT signaling pathways. Moreover, the mRNA expression of NLRC5 was decreased in the blood of PD patients compared to healthy subjects. Therefore, we suggest that NLRC5 promotes neuroinflammation and dopaminergic degeneration in PD and may serve as a marker of glial activation.

NRSF regulates age-dependently cognitive ability and its conditional knockout in APP/PS1 mice moderately alters AD-like pathology.

NRSF/REST (neuron-restrictive silencer element, also known as repressor element 1-silencing transcription factor), plays a key role in neuronal homeostasis as a transcriptional repressor of neuronal genes. NRSF/REST relates to cognitive preservation and longevity of humans, but its specific functions in age-dependent and Alzheimer's disease (AD)-related memory deficits remain unclear. Here, we show that conditional NRSF/REST knockout either in the dorsal telencephalon or specially in neurons induced an age-dependently diminished retrieval performance in spatial or fear conditioning memory tasks and altered hippocampal synaptic transmission and activity-dependent synaptic plasticity. The NRSF/REST deficient mice were also characterized by an increase of activated glial cells, complement C3 protein and the transcription factor C/EBPß in the cortex and hippocampus. Reduction of NRSF/REST by conditional depletion upregulated the activation of astrocytes in APP/PS1 mice, and increased the C3-positive glial cells, but did not alter the Aß loads and memory retrieval performances of 6- and 12-month-old APP/PS1 mice. Simultaneously, overexpression of NRSF/REST improved cognitive abilities of aged wild type, but not in AD mice. These findings demonstrated that NRSF/REST is essential for the preservation of memory performance and activity-dependent synaptic plasticity during aging and takes potential roles in the onset of age-related memory impairments. However, while altering the glial activation, NRSF/REST deficiency does not interfere with the Aß deposits and the electrophysiological and cognitive AD-like pathologies.

Factors correlated with targeted prevention for prediabetes classified by impaired fasting glucose, impaired glucose tolerance, and elevated HbA1c: A population-based longitudinal study.

Background: There is still controversy surrounding the precise characterization of prediabetic population. We aim to identify and examine factors of demographic, behavioral, clinical, and biochemical characteristics, and obesity indicators (anthropometric characteristics and anthropometric prediction equation) for prediabetes according to different definition criteria of the American Diabetes Association (ADA) in the Chinese population. Methods: A longitudinal study consisted of baseline survey and two follow-ups was conducted, and a pooled data were analyzed. Prediabetes was defined as either impaired fasting glucose (IFG), impaired glucose tolerance (IGT), or elevated glycosylated hemoglobin (HbA1c) according to the ADA criteria. Robust generalized estimating equation models were used. Results: A total of 5,713 (58.42%) observations were prediabetes (IGT, 38.07%; IGT, 26.51%; elevated HbA1c, 23.45%); 9.66% prediabetes fulfilled all the three ADA criteria. Among demographic characteristics, higher age was more evident in elevated HbA1c [adjusted OR (aOR)=2.85]. Female individuals were less likely to have IFG (aOR=0.70) and more likely to suffer from IGT than male individuals (aOR=1.41). Several inconsistency correlations of biochemical characteristics and obesity indicators were detected by prediabetes criteria. Body adiposity estimator exhibited strong association with prediabetes (D10: aOR=4.05). For IFG and elevated HbA1c, the odds of predicted lean body mass exceed other indicators (D10: aOR=3.34; aOR=3.64). For IGT, predicted percent fat presented the highest odds (D10: aOR=6.58). Conclusion: Some correlated factors of prediabetes under different criteria differed, and obesity indicators were easily measured for target identification. Our findings could be used for targeted intervention to optimize preventions to mitigate the obviously increased prevalence of diabetes.

Association of sleep duration and sleep quality with the risk of metabolic syndrome in adults: a systematic review and meta-analysis.

INTRODUCTION: The association between sleep duration and metabolic syndrome (MetS) remains controversial, and few have considered the effects of sleep quality. We performed a meta-analysis to clarify the relationship of sleep duration and sleep quality with the risk of MetS. MATERIAL AND METHODS: We conducted a systematic and comprehensive literature search of electronic databases from inception to 17 February 2022. The effect sizes of covariates from each study were pooled using a random or fixed model, and a restricted cubic spline random-effects meta-analysis was performed to examine the dose-response relationship between sleep duration and MetS. RESULTS: A total of 62 studies were included in this meta-analysis. Compared to normal sleep duration, short sleep duration [odds ratio (OR) = 1.14, 95% confidence interval (CI): 1.10-1.19] and long sleep duration (OR = 1.15, 95% CI: 1.09-1.23) were associated with an increased risk of MetS. The restricted cubic spline analysis indicated that sleep durations of 8.5 h (OR = 0.95, 95% CI: 0.92-0.97) and 11 h (OR = 1.58, 95% CI: 1.31-1.91) were significantly associated with the risk of MetS. The pooled results showed that poor sleep quality (OR = 1.46, 95% CI: 1.03-2.06) and sleep complaints had significant positive associations with MetS. CONCLUSION: Our results demonstrated that short sleep duration increased the risk of developing MetS. Long sleep duration was also associated with MetS, especially for 11 h. 8.5 h can be considered the recommended sleep duration for MetS. Poor sleep quality and sleep complaints were also associated with MetS.

Dimensionality Reduction of Local Field Potential Features with Convolution Neural Network in Neural Decoding: A Pilot Study.

Local field potentials (LFPs) have better long-term stability compared with spikes in brain-machine interfaces (BMIs). Many studies have shown promising results of LFP decoding, but the high-dimensional feature of LFP still hurdle the development of the BMIs to low-cost. In this paper, we proposed a framework of a 1D convolution neural network (CNN) to reduce the dimensionality of the LFP features. For evaluating the performance of this architecture, the reduced LFP features were decoded to cursor position (Center-out task) by a Kalman filter. The Principal components analysis (PCA) was also performed as a comparison. The results showed that the CNN model could reduce the dimensionality of LFP features to a smaller size without significant performance loss. The decoding result based on the CNN features outperformed that based on the PCA features. Moreover, the reduced features by CNN also showed robustness across different sessions. These results demonstrated that the LFP features reduced by the CNN model achieved low cost without sacrificing high-performance and robustness, suggesting that this method could be used for portable BMI systems in the future.

Partial depletion and repopulation of microglia have different effects in the acute MPTP mouse model of Parkinson's disease.

OBJECTIVES: Parkinson's disease (PD) is a common neurodegenerative disorder characterized by the progressive and selective degeneration of dopaminergic neurons. Microglial activation and neuroinflammation are associated with the pathogenesis of PD. However, the relationship between microglial activation and PD pathology remains to be explored. MATERIALS AND METHODS: An acute regimen of MPTP was administered to adult C57BL/6J mice with normal, much reduced or repopulated microglial population. Damages of the dopaminergic system were comprehensively assessed. Inflammation-related factors were assessed by quantitative PCR and Multiplex immunoassay. Behavioural tests were carried out to evaluate the motor deficits in MPTP-challenged mice. RESULTS: The receptor for colony-stimulating factor 1 inhibitor PLX3397 could effectively deplete microglia in the nigrostriatal pathway of mice via feeding a PLX3397-formulated diet for 21 days. Microglial depletion downregulated both pro-inflammatory and anti-inflammatory molecule expression at baseline and after MPTP administration. At 1d post-MPTP injection, dopaminergic neurons showed a significant reduction in PLX3397-fed mice, but not in control diet (CD)-fed mice. However, partial microglial depletion in mice exerted little effect on MPTP-induced dopaminergic injuries compared with CD mice at later time points. Interestingly, microglial repopulation brought about apparent resistance to MPTP intoxication. CONCLUSIONS: Microglia can inhibit PD development at a very early stage; partial microglial depletion has little effect in terms of the whole process of the disease; and microglial replenishment elicits neuroprotection in PD mice.