Atherosclerosis is a slowly progressing inflammatory disease characterized with cholesterol disorder and intimal plaques. Asparagine endopeptidase (AEP) is an endolysosomal protease that is activated under acidic conditions and is elevated substantially in both plasma and plaques of patients with atherosclerosis. However, how AEP accelerates atherosclerosis development remains incompletely understood, especially from the view of cholesterol metabolism. This project aims to reveal the crucial substrate of AEP during atherosclerosis plaque formation and to lay the foundation for developing novel therapeutic agents for Atherosclerosis. Here, we show that AEP is augmented in the atherosclerosis plaques obtained from patients and proteolytically cuts apolipoprotein A1 (APOA1) and impairs cholesterol efflux and high-density lipoprotein (HDL) formation, facilitating atherosclerosis pathologies. AEP is activated in the liver and aorta of apolipoprotein E-null (APOE-null) mice, and deletion of AEP from APOE-/- mice attenuates atherosclerosis. APOA1, an essential lipoprotein in HDL for cholesterol efflux, is cleaved by AEP at N208 residue in the liver and atherosclerotic macrophages of APOE-/- mice. Blockade of APOA1 cleavage by AEP via N208A mutation or its specific inhibitor, #11a, substantially diminishes atherosclerosis in both APOE-/- and LDLR-/- mice. Hence, our findings support that AEP disrupts cholesterol metabolism and accelerates the development of atherosclerosis.

The pathogenesis of Lewy body diseases (LBDs), including Parkinson’s disease (PD), involves α-synuclein (α-Syn) aggregation that originates in peripheral organs and spreads to the brain. PD incidence is increased in individuals with chronic renal failure, but the underlying mechanisms remain unknown. Here we observed α-Syn deposits in the kidneys of patients with LBDs and in the kidney and central nervous system of individuals with end-stage renal disease without documented LBDs. In male mice, we found that the kidney removes α-Syn from the blood, which is reduced in renal failure, causing α-Syn deposition in the kidney and subsequent spread into the brain. Intrarenal injection of α-Syn fibrils induces the propagation of α-Syn pathology from the kidney to the brain, which is blocked by renal denervation. Deletion of α-Syn in blood cells alleviates pathology in α-Syn A53T transgenic mice. Thus, the kidney may act as an initiation site for pathogenic α-Syn spread, and compromised renal function may contribute to the onset of LBDs. Yuan et al. find that the kidney can serve as a site of initiation for the spread of pathological α-synuclein to the brain, contributing to the development of Parkinson’s disease (PD) and providing a mechanistic link between PD and renal dysfunction.

The brain plays a central role in aging and longevity in diverse model organisms. Morphological and functional alteration in the aging brain elicits age-associated neuronal dysfunctions. However, the primary mechanism deteriorating the brain functions to regulate the aging process remains incompletely understood. Here, it is shown that neuronal CCAAT/enhancer binding protein β (C/EBPβ) escalation during aging dictates the frailty and lifespan via inactivating nicotinamide phosphoribosyltransferase (NAMPT). Upregulated C/EBPβ drives neuronal senescence and neuronal loss, associated with NAMPT fragmentation by active asparagine endopeptidase (AEP), leading to nicotinamide adenine dinucleotide (NAD+) depletion. Knockout of AEP or expression of AEP-resistant NAMPT N136A mutant significantly elongates the lifespan of neuronal-specific Thy 1-C/EBPβ transgenic mice. Overexpression of the C. elegans C/EBPβ ortholog cebp-2 in neurons shortens lifespan and decreases NAD+ levels, which are restored by feeding nicotinamide mononucleotide (NMN) or AEP inhibitor #11a. Feeding NMN or #11a substantially ameliorates the cognitive and motor impairments of Thy 1-C/EBPβ mice and increases the life expectancy. Notably, #11a demonstrates a better therapeutic effect than NMN in improving aging phenotype in Thy 1-C/EBPβ transgenic mice, which show accelerated aging features. Hence, blockade of AEP via therapeutic intervention may provide an unprecedented strategy for fighting aging and various age-associated diseases.

Cerebrotendinous xanthomatosis (CTX) is an autosomal recessive lipid storage disease characterized by the accumulation of cholestanol. CTX patients often suffer from cognitive impairment. We found that serum cholestanol levels are higher in Alzheimer’s disease (AD) patients than in control subjects. Thus, we tested whether cholestanol regulates the pathogenesis of AD. Cholestanol promotes tau fragmentation and hyperphosphorylation by activating asparagine endopeptidase (AEP). AEP knockdown alleviates cholestanol-induced tau fragmentation and phosphorylation. Feeding cholestanol to tau P301S mice aggravates tau pathology and behavioral defects, while knockout of AEP ameliorates cholestanol-induced tau pathology and behavioral defects in tau P301S mice. These results highlight the role of AEP-mediated tau cleavage in cholestanol-induced tau pathology and cognitive decline. The data also identify the potential therapeutic target of AEP in AD, particularly in AD patients with elevated serum cholestanol levels.

The abnormal deposition of amyloid β (Aβ), produced by proteolytic cleavage events of amyloid precursor protein involving the protease γ-secretase and subsequent polymerization into amyloid plaques, plays a key role in the neuropathology of Alzheimer’s disease (AD). Here we show that ErbB3 binding protein 1 (EBP1)/proliferation-associated 2G4 (PA2G4) interacts with presenilin, a catalytic subunit of γ-secretase, inhibiting Aβ production. Mice lacking forebrain Ebp1/Pa2g4 recapitulate the representative phenotypes of late-onset sporadic AD, displaying an age-dependent increase in Aβ deposition, amyloid plaques and cognitive dysfunction. In postmortem brains of patients with AD and 5x-FAD mice, we found that EBP1 is proteolytically cleaved by asparagine endopeptidase at N84 and N204 residues, compromising its inhibitory effect on γ-secretase, increasing Aβ aggregation and neurodegeneration. Accordingly, injection of AAV2-Ebp1 wild-type or an asparagine endopeptidase-uncleavable mutant into the brains of 5x-FAD mice decreased Aβ generation and alleviated the behavioral impairments. Thus, our study suggests that EBP1 acts as an inhibitor of γ-secretase on amyloid precursor protein cleavage and preservation of functional EBP1 could be a therapeutic strategy for AD. Using a genome-wide association studies approach and patient brain tissue, Kim, Hwang et al. link Ebp1 to Alzheimer’s disease (AD). They show that a conditional Ebp1 knockout mouse model mimics phenotypes of sporadic AD and find that EBP1 reduces amyloid β production by inhibiting γ-secretase.

Dopaminergic neurons in the substantia nigra pars compacta (SNpc) demonstrate regionally selective susceptibility in Parkinson's disease (PD) compared to those in the ventral tegmental area (VTA). However, the molecular mechanism for this distinct vulnerability remains unclear. Here, it is shown that Legumain, also known as asparagine endopeptidase (AEP), is activated in a subgroup of SRY-box transcription factor 6 /Aldehyde dehydrogenase 1 family member A1, (Sox6(+)/ALDH1A1(+)) neurons in the ventral tier of the SNpc and cleaves Sox6 and ALDH1A1, leading to repression of Special AT-rich sequence binding protein 1 (Satb1) that is a dimeric/tetrameric transcription factor specifically binding to AT-rich DNA sequences, and toxic dopamine metabolite accumulation. AEP cuts Sox6 and ALDH1A1 in dopaminergic neurons that project to the locus coeruleus (LC), abolishing Sox6's transcriptive and ALDH1A1's enzymatic activities. Co-expressing AEP-truncated Sox6 and ALDH1A1 fragments in 3-month-old A53T SNCA transgenic mice accelerates dopamine degeneration, whereas expressing AEP-resistant Sox6 N336A/N446A and ALDH1A1 N220A mutants alleviates rotenone-induced PD pathologies. Hence, different circuitries and intrinsic properties of dopaminergic neurons in the SNpc and VTA render differential predispositions in PD.

Parkinson's disease (PD) is characterized by the deposition of misfolded α-synuclein (α-syn) in the brain. Converging evidence indicates that the intracellular transmission and subsequent templated amplification of α-syn are involved in the onset and progression of PD. However, the molecular mechanisms underlying the cell-to-cell transmission of pathological α-syn remain poorly understood. Microglia is highly activated in the brains of PD patients. Here, it is shown that depletion of microglia slows the spread of pathological α-syn pathology in mice injected with α-syn fibrils. Microglia phagocytose α-syn fibrils and transform them into more toxic species. The phagocytosis of α-syn fibrils by microglia is partially mediated by triggering a receptor expressed on myeloid cells 2 (TREM2), a transmembrane protein expressed on the surface of microglia. The endocytosed α-syn fibrils are then cleaved by the lysosomal proteinase asparagine endopeptidase (AEP) to generate truncated α-syn 1-103 fibrils with enhanced seeding activity. Knockout of TREM2 and AEP impedes the endocytosis and cleavage of α-syn fibrils, respectively. The results demonstrate that TREM2-mediated phagocytosis of α-syn fibrils by microglia and subsequent AEP-mediated cleavage of α-syn fibrils contribute to the spread of α-syn in the brain. Blocking either of these two steps attenuates the progression of α-syn pathology.

The bridging integrator 1 (BIN1) gene is an important risk locus for late-onset Alzheimer's disease (AD). BIN1 protein has been reported to mediate tau pathology, but the underlying molecular mechanisms remain elusive. Here, we show that neuronal BIN1 is cleaved by the cysteine protease legumain at residues N277 and N288. The legumain-generated BIN1 (1-277) fragment is detected in brain tissues from AD patients and tau P301S transgenic mice. This fragment interacts with tau and accelerates its aggregation. Furthermore, the BIN1 (1-277) fragment promotes the propagation of tau aggregates by enhancing clathrin-mediated endocytosis (CME). Overexpression of the BIN1 (1-277) fragment in tau P301S mice facilitates the propagation of tau pathology, inducing cognitive deficits, while overexpression of mutant BIN1 that blocks its cleavage by legumain halts tau propagation. Furthermore, blocking the cleavage of endogenous BIN1 using the CRISPR/Cas9 gene-editing tool ameliorates tau pathology and behavioral deficits. Our results demonstrate that the legumain-mediated cleavage of BIN1 plays a key role in the progression of tau pathology. Inhibition of legumain-mediated BIN1 cleavage may be a promising therapeutic strategy for treating AD.

ObjectiveThis study aims to develop and validate a prediction model for evaluating the social participation in the community middle-aged and older adult stroke survivors.MethodsThe predictive model is based on data from the China Health and Retirement Longitudinal Study (CHARLS), which focused on individuals aged 45 years or older. The study utilized subjects from the CHARLS 2015 and 2018 wave, eighteen factors including socio-demographic variables, behavioral and health status, mental health parameters, were analyzed in this study. To ensure the reliability of the model, the study cohort was randomly split into a training set (70%) and a validation set (30%). The Least Absolute Shrinkage and Selection Operator (LASSO) regression analysis was used to identify the most effective predictors of the model through a 10-fold cross-validation. The logistic regression model was employed to investigate the factors associated with social participation in stroke patients. A nomogram was constructed to develop a prediction model. Calibration curves were used to assess the accuracy of the nomogram model. The model’s performance was evaluated using the area under the curve (AUC) and decision curve analysis (DCA).ResultA total of 1,239 subjects with stroke from the CHARLS database collected in 2013 and 2015 wave were eligible in the final analysis. Out of these, 539 (43.5%) subjects had social participation. The model considered nineteen factors, the LASSO regression selected eleven factors, including age, gender, residence type, education level, pension, insurance, financial dependence, physical function (PF), self-reported healthy,cognition and satisfaction in the prediction model. These factors were used to construct the nomogram model, which showed a certain extent good concordance and accuracy. The AUC values of training and internal validation sets were 0.669 (95%CI 0.631–0.707) and 0.635 (95% CI 0.573–0.698), respectively. Hosmer–Lemeshow test values were p = 0.588 and p = 0.563. Calibration curves showed agreement between the nomogram model and actual observations. ROC and DCA indicated that the nomogram had predictive performance.ConclusionThe nomogram constructed in this study can be used to evaluate the probability of social participation in middle-aged individuals and identify those who may have low social participation after experiencing a stroke.

Cerebrotendinous xanthomatosis (CTX), an autosomal recessive disorder characterized by high levels of cholestanol in the blood and accumulation of cholestanol in multiple tissues, especially the brain, often presents in parkinsonism. However, it remains unknown whether cholestanol plays a role in the pathogenesis of sporadic Parkinson’s disease (PD). Here, we show that the levels of serum cholestanol in patients with sporadic PD are higher than those in control participants. Cholestanol activates the protease asparagine endopeptidase (AEP) and induces the fragmentation of α-synuclein (α-syn) and facilitates its aggregation. Furthermore, cholestanol promotes the spreading of α-syn pathology in a mouse model induced by intrastriatal injection of α-syn fibrils. KO of AEP or administration of an AEP inhibitor ameliorates α-syn pathology, degeneration of the nigrostriatal dopaminergic pathway, and PD-like motor symptoms. These results not only indicate that cholestanol contributes to the aggregation and spreading of α-syn by activating AEP but also reveal an opportunity for treating PD with AEP inhibitors.

脑腱黄瘤病(Cerebrotendinous xanthomatosis,CTX)是一种少见的常染色体隐性遗传性脂质贮积病,由Bogaert在1937年首次报道[1].CTX是由CYP27A1基因突变引起的脂质代谢障碍性疾病.CYP27A1又称细胞色素P45027A1,其功能是催化多种甾醇的羟基化,参与胆汁酸和维生素D的合成[2-4].CYP27A1基因突变会影响CYP27A1的酶活性,导致胆汁酸合成障碍,两种主要的胆汁酸包括胆酸(Cholic acid,CA)和鹅去氧胆酸(Chenodeoxycholic acid,CD-CA)生成减少.CDCA的减少会激活胆汁酸合成途径中的关键酶 CYP7A1,促进中间产物 7α-hydroxy-4-cholesten-3-one的生成,此中间产物进一步代谢形成胆甾烷醇和其他甾醇类物质,蓄积在脑、跟腱、晶状体及其它器官中,引起进行性加重的神经系统症状、肌腱黄色瘤、双侧早发性白内障等[5-10].

Background: The diagnosis and treatment rate of Parkinson disease (PD) with depression has a low diagnostic rate, and there is no consensus on the choice of treatment mode. This study evaluates the global research trends of scientific outputs related to depression in PD from multiple perspectives, using a bibliometric analysis and visualization tool to scientifically analyze the knowledge from the literature. Methods: Literature related to depression in PD published from 2012 to 2021 was included and selected from the Web of Science Core Collection database in October 2021. CiteSpace software was used to visualize and analyze co-occurrence analyses for countries, institutions, authors, and keywords. Results: A total of 4533 articles from the Web of Science database were included. The United States made the largest contribution with the majority of publications (1215; 29.40%). Toronto University was the most productive institution. PD, depression, quality of life, dementia, nonmotor symptom, prevalence, anxiety, Alzheimer disease, symptom, and disorder would be significantly correlated with depression in PD. The current hot spots in this field focus on the following: risk factors for depression in PD, assessment scale of depression in PD, and rehabilitation of depression in PD. Conclusions: This analysis not only reveals the current research trends and hotspots but also provides some instructive suggestions on the development of depression in PD.

Abstract Background A novel coronavirus, SARS-CoV-2, has recently emerged and caused the rapid spread of COVID-19 worldwide. Methods We did a retrospective study and included COVID-19 patients admitted to Renmin Hospital of Wuhan University between February 1 and February 29, 2020. Antibody assay was conducted to detect COVID-19 envelope protein E and nucleocapsid protein N antigen. Results 112 patients were recruited with symptoms of fever, cough, fatigue, myalgia, and diarrhoea. All patients underwent antibody tests. Fifty-eight (51.79%) were positive for both IgM and IgG, 7 (6.25%) were negative for both antibodies, 1 (0.89%) was positive for only IgM, and 46 (41.07%) were positive for only IgG. IgM antibody appeared within a week post disease onset, and lasted for one month and gradually decreased, while IgG antibody was produced 10 days after infection, and lasted for a longer time. However, no significant difference in level of IgM and IgG antibody between positive and negative patients of nucleic acid test after treatment was found. Conclusions Our results indicate that serological tests could be powerful approach for the early diagnosis of COVID-19.

L-DOPA-induced dyskinesia (LID) is a major complication of long-term dopamine replacement therapy in Parkinson's disease. Characteristic neural oscillation and abnormal activity of striatal projection neurons (SPNs) are typical pathological events of LID, which would be reliable biomarkers for assessment of novel anti-dyskinetic approach if fully profiled. Glutamate dysregulation plays a critical role in the development of LID, and the group II metabotropic glutamate receptors (mGluR2/3) is believed to regulate the release of glutamate on the presynaptic terminals and inhibits postsynaptic excitation. However, the anti-dyskinetic effect of modulating mGluR2/3 is still unclear. In this study, rats with unilateral dopaminergic lesion were injected with L-DOPA (12 mg/kg, i.p.) for seven days, while motor behavior was correlated with in vivo electrophysiology analyzing LFP and single-cell activity in both primary motor cortex and dorsolateral striatum. Our study showed that as LID established, high γ oscillation (hγ) predominated during LID, the number of unstable responses of SPN to dopamine increased, and the coherence between these patterns of oscillation and spiking activity also increased. We found that pretreatment of NMDA receptor antagonist, amantadine 60 mg/kg, i.p. (AMAN) significantly reduced abnormal involuntary movements (AIMs), in parallel with the reduction of hγ oscillation, and more markedly with a decrease in unstable responses of SPNs. In contrast, a mGluR2/3 agonist, LY354740 12 mg/kg, i.p. (LY) significantly shortened the duration of LID but merely exhibited a weak effect in diminishing the intensity of LID or reversing SPN responses. Together results indicate that AIMs in the rat model of PD are associated with abnormal corticostriatal signaling, which could be reversed by NMDAR antagonism more efficiently than mGluR2/3 agonism.

Glutamate overactivity in basal ganglia critically contributes to the exacerbation of dopaminergic neuron degeneration in Parkinson's disease (PD). Activation of group II metabotropic glutamate receptors (mGlu2/3 receptors), which can decrease excitatory glutamate neurotransmission, provides an opportunity to slow down the degeneration of the dopaminergic system. However, the roles of mGlu2/3 receptors in relation to PD pathology were partially recognized. By using mGlu2/3 receptors agonist (LY354740) and mGlu2/3 receptors antagonist (LY341495) in mice challenged with different cumulative doses of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), we demonstrated that systemic injection of LY354740 reduced the level of extracellular glutamate and the extent of nigro-striatal degeneration in both acute and sub-acute MPTP mice, while LY341495 amplified the lesions in sub-acute MPTP mice only. LY354740 treatment improved behavioral dysfunctions mainly in acute MPTP mice and LY341495 treatment seemed to aggravate motor deficits in sub-acute MPTP mice. In addition, ligands of mGlu2/3 receptors also influenced the total amount of glutamate and dopamine in brain tissue. Interestingly, compared with normal mice, MPTP-treated mice abnormally up-regulated the expression of polo-like kinase 2 (PLK2)/pS129 α-synuclein and phosphorylation of Fyn/N-methyl-D-aspartate receptor subunit 2A/2B (GluN2A/2B). Both acute and sub-acute MPTP mice treated with LY354740 dose-dependently reduced all the above abnormal expression. Compared with MPTP mice treated with vehicle, mice pretreated with LY341495 exhibited much higher expression of p-Fyn Tyr416/p-GluN2B Tyr1472 and PLK2/pS129 α-synuclein in sub-acute MPTP mice models. Thus, our current data indicated that mGlu2/3 receptors ligands could influence MPTP-induced toxicity, which supported a role for mGlu2/3 receptors in PD pathogenesis.

Patients with Coronavirus Disease 2019 (COVID-19) often have clinical characteristics, such as chest tightness and dyspnea. Continuous, unresolved dyspnea often indicates the progression of lung lesions. The mechanism that underlies the chest distress and dyspnea in patients with COVID-19 is still unclear. Chest CT has a higher sensitivity and can play an essential role in the diagnosis and treatment of the disease. However, our clinical observations showed that although some patients had significant chest distress and dyspnea, the lesions that were observed in the lungs during computed tomography were milder and not completely consistent with clinical symptoms. We analyzed the clinical characteristics, laboratory test results, and imaging findings of these patients. We found that extensive inflammation of the bilateral and respiratory bronchioles in patients with COVID-19 due to excessive activation of proinflammatory cytokines and chemotactic aggregation of T-lymphocytes at the site of inflammation are possible mechanisms underlying chest distress and dyspnea in patients with COVID-19. Short-time and lose-dose use of corticosteroid may be helpful to treat chest tightness and dyspnea in mild COVID-19 patients. Through this study, we aimed to improve our understanding of the pathogenesis of COVID-19.

We firstly reported a case of acute myelitis in a SARS-CoV-2-infected patient. A 66-year-old man with COVID-19 was admitted with acute flaccid paralysis of bilateral lower limbs and urinary and bowel incontinence. All serum microbiological studies were negative except for SARS-CoV-2 nucleic acid testing. Clinical findings could be ascribed to a post-infectious acute myelitis. He was receiving treatment with ganciclovir, lopinavir/ritonavir, moxifloxacin, dexamethasone, human immunoglobulin and mecobalamin. With a diagnosis of post-infectious acute myelitis and comprehensive treatment, paralysis of bilateral lower extremities ameliorated. After two times negative novel coronavirus RNA nasopharyngeal swabs tests, he was discharged and transferred to a designated hospital for isolation treatment and rehabilitation therapy.

BACKGROUND:A novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has recently emerged and caused the rapid spread of coronavirus disease 2019 (COVID-19) worldwide.METHODS:We did a retrospective study and included COVID-19 patients admitted to Renmin Hospital of Wuhan University between 1 February and 29 February 2020. Antibody assay was conducted to detect COVID-19 envelope protein E and nucleocapsid protein N antigen.RESULTS:One hundred twelve patients were recruited with symptoms of fever, cough, fatigue, myalgia, and diarrhea. All patients underwent antibody tests. Fifty-eight (51.79%) were positive for both immunoglobulin M (IgM) and immunoglobulin G (IgG), 7 (6.25%) were negative for both antibodies, 1 (0.89%) was positive for only IgM, and 46 (41.07%) were positive for only IgG. IgM antibody appeared within a week post-disease onset, lasted for 1 month, and gradually decreased, whereas IgG antibody was produced 10 days after infection and lasted for a longer time. However, no significant difference in levels of IgM and IgG antibodies between positive and negative patients of nucleic acid test after treatment was found.CONCLUSIONS:Our results indicate that serological tests could be a powerful approach for the early diagnosis of COVID-19.