Exercised-enriched blood plasma rescues hippocampal impairments and cognitive deficits in an Alzheimer's disease model.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder, and moderate exercise holds promise in ameliorating the ongoing neurodegeneration and cognitive decline. Here, we investigated whether exercise-enriched blood plasm could yield a beneficial therapeutic effect on AD pathologies and cognitive decline in transgenic AD (P301S) mice. In this investigation, a cohort of 2-month-old C57BL/6 mice were granted continuous access to either a running wheel or a fixed wheel for 6 weeks. After that, their plasmas were extracted and subsequently injected intravenously into 4.5-month-old P301S mice biweekly over a 6-week period. A comprehensive methodology was then employed, integrating behavioral tests, pathology assessments, and biochemical analyses to unveil the potential anti-dementia implications of exercise-enriched blood plasma in P301S mice. Upon systemic administration, the findings revealed a noteworthy attenuation of hippocampus-dependent behavioral impairments in P301S mice. Conversely, blood plasma from sedentary counterparts exhibited no discernible impact. These effects were intricately associated with the mitigation of neuroinflammation, the augmentation of hippocampal adult neurogenesis, and a reduction of synaptic impairments following the administration of exercise-enriched blood plasma. These findings advance the proposition that administering exercise-enriched blood plasma may serve as an effective prophylactic measure against AD, opening avenues for further exploration and potential therapeutic interventions.

Ankylosing spondylitis coexisting with Clonorchis sinensis infection: A case report.

BACKGROUND: Ankylosing spondylitis (AS) is a chronic immune-mediated inflammatory disease. The prevailing theory links AS onset to infections in susceptible individuals. Furthermore, infections may impair the immune responses. Numerous studies have investigated links between AS and various infections-bacterial, viral, fungal, and other microorganism infections. However, limited attention has been given to the association between AS and Clonorchis sinensis (C. sinensis) infection. CASE SUMMARY: A 27-year-old male with a 10-yr history of AS presented to our hospital with inflammatory lower back pain as the primary manifestation. Ten years ago, the patient had achieved a stable condition after treatment with biological agents. However, he experienced a recurrence of lumbosacral pain with an unexplained cause 10 d before hospital admission. A lumbosacral magnetic resonance imaging (MRI) scan revealed bone marrow edema in the left sacroiliac joint, and laboratory indicators were elevated. Moreover, the presence of C. sinensis eggs was detected in the stool. The patient was prescribed praziquantel, resulting in the disappearance of C. sinensis eggs in subsequent routine stool tests and relief from lumbosacral pain. A follow-up MRI scan performed after 4 months revealed a reduction in bone marrow edema around the left sacroiliac joint. CONCLUSION: C. sinensis infections could potentially trigger the exacerbation of AS. Clinicians should pay attention to investigating the presence of infections.

P25/CDK5-mediated Tau Hyperphosphorylation in Both Ipsilateral and Contralateral Cerebra Contributes to Cognitive Deficits in Post-stroke Mice.

OBJECTIVE: Post-stroke cognitive impairment (PSCI) develops in approximately one-third of stroke survivors and is associated with ingravescence. Nonetheless, the biochemical mechanisms underlying PSCI remain unclear. The study aimed to establish an ischemic mouse model by means of transient unilateral middle cerebral artery occlusions (MCAOs) and to explore the biochemical mechanisms of p25/cyclin-dependent kinase 5 (CDK5)-mediated tau hyperphosphorylation on the PSCI behavior. METHODS: Cognitive behavior was investigated, followed by the detection of tau hyperphosphorylation, mobilization, activation of kinases and/or inhibition of phosphatases in the lateral and contralateral cerebrum of mice following ischemia in MACO mice. Finally, we treated HEK293/tau cells with oxygen-glucose deprivation (OGD) and a CDK5 inhibitor (Roscovitine) or a GSK3ß inhibitor (LiCl) to the roles of CDK5 and GSK3ß in mediating ischemia-reperfusion-induced tau phosphorylation. RESULTS: Ischemia induced cognitive impairments within 2 months, as well as causing tau hyperphosphorylation and its localization to neuronal somata in both ipsilateral and contralateral cerebra. Furthermore, p25 that promotes CDK5 hyperactivation had significantly higher expression in the mice with MCAO than in the shamoperation (control) group, while the expression levels of protein phosphatase 2 (PP2A) and the phosphorylation level at Tyr307 were comparable between the two groups. In addition, the CDK5 inhibitor rescued tau from hyperphosphorylation induced by OGD. CONCLUSION: These findings demonstrate that upregulation of CDK5 mediates tau hyperphosphorylation and localization in both ipsilateral and contralateral cerebra, contributing to the pathogenesis of PSCI.

Glycogen Synthase Kinase-3ß, NLRP3 Inflammasome, and Alzheimer's Disease.

Alzheimer's disease (AD) is the most prevalent cause of dementia worldwide. Because of the progressive neurodegeneration, individual cognitive and behavioral functions are impaired, affecting the quality of life of millions of people. Although the exact pathogenesis of AD has not been fully elucidated, amyloid plaques, neurofibrillary tangles (NFTs), and sustaining neuroinflammation dominate its characteristics. As one of the major tau kinases leading to hyperphosphorylation and aggregation of tau, glycogen synthase kinase-3ß (GSK-3ß) has been drawing great attention in various AD studies. Another research focus of AD in recent years is the inflammasome, a multiprotein complex acting as a regulator in immunological reactions to exogenous and endogenous danger signals, of which the Nod-like receptor (NLR) family, pyrin domain-containing 3 (NLRP3) inflammasome has been studied mostly in AD and proven to play a significant role in AD development by its activation and downstream effects such as caspase-1 maturation and interleukin (IL)-1ß release. Studies have shown that the NLRP3 inflammasome is activated in a GSK-3ß-dependent way and that inhibition of the NLRP3 inflammasome downregulates GSK-3ß, suggesting that these two important proteins are closely related. This article reviews the respective roles of GSK-3ß and the NLRP3 inflammasome in AD as well as their relationship and interaction.

Inactivation of ERK1/2-CREB Pathway Is Implicated in MK801-induced Cognitive Impairment.

OBJECTIVE: Schizophrenia (SZ) is associated with cognitive impairment, and it is known that the activity of cAMP response element binding protein (CREB) decreases in the brain of SZ patients. The previous study conducted by the investigators revealed that the upregulation of CREB improves the MK801-related SZ cognitive deficit. The present study further investigates the mechanism on how CREB deficiency is associated with SZ-related cognitive impairment. METHODS: MK-801 was used to induce SZ in rats. Western blotting and immunofluorescence were performed to investigate CREB and the CREB-related pathway implicated in MK801 rats. The long-term potentiation and behavioral tests were performed to assess the synaptic plasticity and cognitive impairment, respectively. RESULTS: The phosphorylation of CREB at Ser133 decreased in the hippocampus of SZ rats. Interestingly, among the upstream kinases of CREB, merely ERK1/2 was downregulated, while CaMKII and PKA remained unchanged in the brain of MK801-related SZ rats. The inhibition of ERK1/2 by PD98059 reduced the phosphorylation of CREB-Ser133, and induced synaptic dysfunction in primary hippocampal neurons. Conversely, the activation of CREB attenuated the ERK1/2 inhibitor-induced synaptic and cognitive impairment. CONCLUSION: These present findings partially suggest that the deficiency of the ERK1/2-CREB pathway is involved in MK801-related SZ cognitive impairment. The activation of the ERK1/2-CREB pathway may be therapeutically useful for treating SZ cognitive deficits.

Epitranscriptomic profiling of m6A RNA methylation in renal epithelial tubular cells stimulated with calcium oxalate crystals through microarray analysis.

The aim of this study was to investigate the relationship of m6A RNA methylation to CaOX-induced renal tubular injury. Microarray analysis was performed to detect the difference in mRNA expression and m6A methylation between the injurious groups and controls. We established injurious renal tubular epithelial cell model induced by calcium oxalate crystals (CaOX), and we validated that CaOX could increase the overall m6A methylation levels. By microarray analysis, we identified 5967 differentially expressed mRNAs (2444 were up-regulated and 3523 were down-regulated in the injurious groups) and 6853 differentially methylated mRNAs (4055 were in hypermethylation and 3688 were in hypomethylation in the injurious groups). Four clusters (hyper-up, hyper-down, hypo-up and hypo-down) were further identified via conjoint analysis. Functional analysis revealed that m6A methylation played a crucial role in the development of CaOX through participating multiple processes covering inflammation, oxidative stress, apoptosis, crystal-cell adhesion. We delineated the first transcriptome-wide m6A landscape of injurious renal tubular cells in high-CaOX environment. We identified a series of mRNAs of renal tubular epithelial cells with differential expression and m6A methylation between the CaOX-treated groups and controls.

CIP2A deficiency promotes depression-like behaviors in mice through inhibition of dendritic arborization.

Major depressive disorder (MDD) is a severe mental illness. Decreased brain plasticity and dendritic fields have been consistently found in MDD patients and animal models; however, the underlying molecular mechanisms remain to be clarified. Here, we demonstrate that the deletion of cancerous inhibitor of PP2A (CIP2A), an endogenous inhibitor of protein phosphatase 2A (PP2A), leads to depression-like behaviors in mice. Hippocampal RNA sequencing analysis of CIP2A knockout mice shows alterations in the PI3K-AKT pathway and central nervous system development. In primary neurons, CIP2A stimulates AKT activity and promotes dendritic development. Further analysis reveals that the effect of CIP2A in promoting dendritic development is dependent on PP2A-AKT signaling. In vivo, CIP2A deficiency-induced depression-like behaviors and impaired dendritic arborization are rescued by AKT activation. Decreased CIP2A expression and impaired dendrite branching are observed in a mouse model of chronic unpredictable mild stress (CUMS). Indicative of clinical relevance to humans, CIP2A expression is found decreased in transcriptomes from MDD patients. In conclusion, we discover a novel mechanism that CIP2A deficiency promotes depression through the regulation of PP2A-AKT signaling and dendritic arborization.

Imaging characteristics of pulmonary BCG/TB infection in patients with chronic granulomatous disease.

In China, tuberculosis (TB) is endemic and the Bacillus Callmette-Güerin (BCG) vaccine is administered to all the newborns, which may lead to BCG infection in patients with chronic granulomatous disease (CGD). Infection of BCG/TB in CGD patients can be fatal and pulmonary is the most affected organ. Our objective was to assess the imaging of pulmonary BCG/TB infection in CGD. We screened 169 CGD patients and identified the patients with pulmonary BCG/TB infection. BCG infection was diagnosis according to the vaccination history, local infection manifestation, acid-fast bacilli staining, specific polymerase chain reaction, and/or spoligotyping. PPD, T-SPOT and acid-fast bacilli staining were used for diagnosis of TB. Totally 58 patients were identified, including TB (n = 7), solely BCG (n = 18), BCG + bacterial (n = 20), and BCG + fungi (n = 13). The onset of BCG disease was much earlier than TB. For those patients only with BCG, lymphadenopathy was the first and most prevalent feature. The most found location was the left axilla, followed by the ipsilateral cervical areas and mediastinal or hilar area. On chest CT, ground-glass opacities, multiple nodules and pulmonary scarring were the most common findings. For TB patients, the pulmonary infections were more serious, including large masses, severe lymphadenopathy, and extensive pulmonary fibrosis. Pulmonary infection of BCG were more common than TB in CGD patients, but much less severe.

Zinc in Regulating Protein Kinases and Phosphatases in Neurodegenerative Diseases.

Zinc is essential for human growth and development. As a trace nutrient, zinc plays important roles in numerous signal transduction pathways involved in distinct physiologic or pathologic processes. Protein phosphorylation is a posttranslational modification which regulates protein activity, degradation, and interaction with other molecules. Protein kinases (PKs) and phosphatases (PPs), with their effects of adding phosphate to or removing phosphate from certain substrates, are master regulators in controlling the phosphorylation of proteins. In this review, we summarize the disturbance of zinc homeostasis and role of zinc disturbance in regulating protein kinases and protein phosphatases in neurodegenerative diseases, with the focus of that in Alzheimer's disease, providing a new perspective for understanding the mechanisms of these neurologic diseases.

External validation of efficacy and reliability of different retrograde intrarenal surgery (RIRS) scoring systems for pediatric nephrolithiasis.

INTRODUCTION: Retrograde Intrarenal Surgery (RIRS) is one of minimally invasive procedures for pediatric upper urinary stones. However, a RIRS predictive system for children to evaluate postoperative stone free rate (SFR) is still unavailable. OBJECTIVE: The aim of this study is to validate the efficacy and reliability of different RIRS scoring systems for children. STUDY DESIGN: We collected clinical data of 137 pediatric patients treated with RIRS in our center between 2014 and 2021. All the predictors were acquired by preoperative non-contrast CT or CT urography. Receiver Operative Curve (ROC) and Area Under Curve (AUC) were showed to compare the predictive power of different models. RESULTS: A total of 162 RIRS procedures were performed for these 137 pediatric patients. Median surgical duration, irrigation volume and hospitalization were 30 (20, 40) min, 500 (300, 1000) ml and 6 (4, 7) days, respectively. Overall SFR and complication rate was 79.6% (129/162) and 29.2% (40/137), respectively. Significant difference was detected between non-stone free group and stone free group in terms of stone complexity (p < 0.001), cumulative stone sizes [2.3 (2.0, 3.5) cm vs. 1.5 (1.0, 2.0) cm, p < 0.001], RUS groups (p < 0.001), S-ReSC groups (p < 0.001) and RIRS nomogram score [10 (8, 12) vs. 23 (18, 25), p < 0.001]. Among them, RIRS nomogram presented with the maximum AUC values in comparison with the other two systems (RUS: 0.944 vs. 0.874, p = 0.001; S-ReSC: 0.944 vs. 0.808, p < 0.001). DISCUSSION: We reported the largest sample size of pediatric patients treated with RIRS in our center. Similar with previous studies, RIRS is an efficacious and safe option for pediatric patients. RIRS nomogram showed the best predictive outcome due to the inclusion of multiple parameters, but an innovative predictive system based on pediatric clinical data is warranted in the future. CONCLUSION: Among the three scoring systems, RIRS nomogram showed the most optimal predictive power of postoperative SFR for pediatric patients.

Neuronal C/EBPß/AEP pathway shortens life span via selective GABAnergic neuronal degeneration by FOXO repression.

The age-related cognitive decline of normal aging is exacerbated in neurodegenerative diseases including Alzheimer's disease (AD). However, it remains unclear whether age-related cognitive regulators in AD pathologies contribute to life span. Here, we show that C/EBPß, an Aß and inflammatory cytokine-activated transcription factor that promotes AD pathologies via activating asparagine endopeptidase (AEP), mediates longevity in a gene dose-dependent manner in neuronal C/EBPß transgenic mice. C/EBPß selectively triggers inhibitory GABAnergic neuronal degeneration by repressing FOXOs and up-regulating AEP, leading to aberrant neural excitation and cognitive dysfunction. Overexpression of CEBP-2 or LGMN-1 (AEP) in Caenorhabditis elegans neurons but not muscle stimulates neural excitation and shortens life span. CEBP-2 or LGMN-1 reduces daf-2 mutant-elongated life span and diminishes daf-16-induced longevity. C/EBPß and AEP are lower in humans with extended longevity and inversely correlated with REST/FOXO1. These findings demonstrate a conserved mechanism of aging that couples pathological cognitive decline to life span by the neuronal C/EBPß/AEP pathway.

Human tau accumulation promotes glycogen synthase kinase-3ß acetylation and thus upregulates the kinase: A vicious cycle in Alzheimer neurodegeneration.

BACKGROUND: Glycogen synthase kinase-3ß (GSK-3ß) is one of the most effective kinases in promoting tau hyperphosphorylation and accumulation in Alzheimer's disease (AD). However, it is not clear how GSK-3ß activity is regulated during AD progression. METHODS: We firstly used mass spectrometry to identify the acetylation site of GSK-3ß, and then established the cell and animal models of GSK-3ß acetylation. Next, we conducted molecular, cell biological and behavioral tests. Finally, we designed a peptide to test whether blocking tau-mediated GSK-3ß acetylation could be beneficial to AD. FINDINGS: We found that GSK-3ß protein levels increased in the brains of AD patients and the transgenic mice. Overexpressing tau increased GSK-3ß protein level with increased acetylation and decreased ubiquitination-related proteolysis. Tau could directly acetylate GSK-3ß at K15 both in vitro and in vivo. K15-acetylation inhibited ubiquitination-associated proteolysis of GSK-3ß and changed its activity-dependent phosphorylation, leading to over-activation of the kinase. GSK-3ß activation by K15-acetylation in turn exacerbated the AD-like pathologies. Importantly, competitively inhibiting GSK-3ß K15-acetylation by a novel-designed peptide remarkably improved cognitive impairment and the AD-like pathologies in 3xTg-AD mice. INTERPRETATION: Tau can directly acetylate GSK-3ß at K15 which reveals a vicious cycle between tau hyperphosphorylation and GSK-3ß activation. FUNDING: This study was supported in parts by grants from Science and Technology Committee of China (2016YFC1305800), Hubei Province (2018ACA142), Natural Science Foundation of China (91949205, 82001134, 31730035, 81721005), Guangdong Provincial Key S&T Program (018B030336001).

Neuronal ApoE4 stimulates C/EBPß activation, promoting Alzheimer's disease pathology in a mouse model.

ApoE4 is a major genetic risk determinant for Alzheimer's disease (AD) and drives its pathogenesis via Aß-dependent and -independent pathways. C/EBPß, a proinflammatory cytokine-activated transcription factor, is upregulated in AD patients and increases cytokines and δ-secretase expression. Under physiological conditions, ApoE is mainly expressed in glial cells, but its neuronal expression is highly elevated under pathological stresses. However, how neuronal ApoE4 mediates AD pathologies remains incompletely understood. Here we show that ApoE4 activates C/EBPß that subsequently regulates APP, Tau and BACE1 mRNA expression in mouse neurons, driving AD-like pathogenesis. To interrogate the pathological roles of both human ApoE4 and C/EBPß elevation in neurons in the aged brain, we develop neuronal specific Thy1-ApoE4/C/EBPß double transgenic mice. Neuronal ApoE4 strongly activates C/EBPß and augmented δ-secretase subsequently cleaves increased mouse APP and Tau, promoting AD-like pathologies. Notably, Thy1-ApoE4/C/EBPß mice develop amyloid deposits, Tau aggregates and neurodegeneration in an age-dependent manner, leading to synaptic dysfunction and cognitive disorders. Thus, our findings demonstrate that neuronal ApoE4 triggers AD pathogenesis via activating the crucial regulator C/EBPß.

Delta- and beta- secretases crosstalk amplifies the amyloidogenic pathway in Alzheimer's disease.

Asparagine endopeptidase (AEP), a newly identified delta-secretase, simultaneously cleaves both APP and Tau, promoting Alzheimer's disease (AD) pathologies. However, its pathological role in AD remains incompletely understood. Here we show that delta-secretase cleaves BACE1, a rate-limiting protease in amyloid-ß (Aß) generation, escalating its enzymatic activity and enhancing senile plaques deposit in AD. Delta-secretase binds BACE1 and cuts it at N294 residue in an age-dependent manner and elevates its protease activity. The cleaved N-terminal motif is active even under neutral pH and associates with senile plaques in human AD brains. Subcellular fractionation reveals that delta-secretase and BACE1 reside in the endo-lysosomes. Interestingly, truncated BACE1 enzymatic domain (1-294) augments delta-secretase enzymatic activity and accelerates Aß production, facilitating AD pathologies and cognitive impairments in APP/PS1 AD mouse model. Uncleavable BACE1 (N294A) inhibits delta-secretase activity and Aß production and decreases AD pathologies in 5XFAD mice, ameliorating cognitive dysfunctions. Hence, delta- and beta- secretases' crosstalk aggravates each other's roles in AD pathogenesis.

ApoE4 activates C/EBPß/δ-secretase with 27-hydroxycholesterol, driving the pathogenesis of Alzheimer's disease.

ApoE4, an apolipoprotein implicated in cholesterol transport and amyloid-ß (Aß) metabolism, is a major genetic risk determinant for Alzheimer's Disease (AD) and drives its pathogenesis via Aß-dependent and -independent pathways. C/EBPß, a proinflammatory cytokines-activated transcription factor, is upregulated in AD and mediates cytokines and δ-secretase expression. However, how ApoE4 contributes to AD pathogenesis remains incompletely understood. Here we show that ApoE4 and 27-hydroxycholesterol (27-OHC) co-activate C/EBPß/δ-secretase signaling in neurons, mediating AD pathogenesis, and this effect is dependent on neuronal secreted Aß and inflammatory cytokines. Inhibition of cholesterol metabolism with lovastatin diminishes neuronal ApoE4's stimulatory effects. Furthermore, ApoE4 and 27-OHC also mediate lysosomal δ-secretase leakage, activation, secretion and endocytosis. Notably, 27-OHC strongly activates C/EBPß/δ-secretase pathway in human ApoE4-TR mice and triggers AD pathologies and cognitive deficits, which is blocked by C/EBPß depletion. Hence, our findings demonstrate that ApoE4 and 27-OHC additively trigger AD pathogenesis via activating C/EBPß/δ-secretase pathway. Lowering cholesterol levels with statins should benefit the ApoE4 AD carriers.

TrkB receptor cleavage by delta-secretase abolishes its phosphorylation of APP, aggravating Alzheimer's disease pathologies.

Neurotrophins promote neuronal survival and synaptic plasticity via activating the tropomyosin receptor kinases. BDNF and its high-affinity receptor TrkB are reduced in Alzheimer's disease (AD), contributing to progressive cognitive decline. However, how the signaling mediates AD pathologies remains incompletely understood. Here we show that the TrkB receptor binds and phosphorylates APP, reducing amyloid-ß production, which are abrogated by δ-secretase cleavage of TrkB in AD. Remarkably, BDNF stimulates TrkB to phosphorylate APP Y687 residue that accumulates APP in the TGN (Trans-Golgi Network) and diminishes its amyloidogenic cleavage. Delta-secretase cleaves TrkB at N365 and N486/489 residues and abolishes its neurotrophic activity, decreasing p-APP Y687 and altering its subcellular trafficking. Notably, both TrkB and APP are robustly cleaved by δ-secretase in AD brains, accompanied by mitigated TrkB signaling and reduced p-Y687. Blockade of TrkB cleavage attenuates AD pathologies in 5xFAD mice, rescuing the learning and memory. Viral expression of TrkB 1-486 fragment in the hippocampus of APP/PS1 mice facilitates amyloid pathology and mitigates cognitive functions. Hence, δ-secretase cleaves TrkB and blunts its phosphorylation of APP, facilitating AD pathogenesis.

C/EBPß is a key transcription factor for APOE and preferentially mediates ApoE4 expression in Alzheimer's disease.

The apolipoprotein E ε4 (APOE4) allele is a major genetic risk factor for Alzheimer's disease (AD), and its protein product, ApoE4, exerts its deleterious effects mainly by influencing amyloid-ß (Aß) and Tau (neurofibrillary tangles, NFTs) deposition in the brain. However, the molecular mechanism dictating its expression during ageing and in AD remains incompletely clear. Here we show that C/EBPß acts as a pivotal transcription factor for APOE and mediates its mRNA levels in an age-dependent manner. C/EBPß binds the promoter of APOE and escalates its expression in the brain. Knockout of C/EBPß in AD mouse models diminishes ApoE expression and Aß pathologies, whereas overexpression of C/EBPß accelerates AD pathologies, which can be attenuated by anti-ApoE monoclonal antibody or deletion of ApoE via its specific shRNA. Remarkably, C/EBPß selectively promotes more ApoE4 expression versus ApoE3 in human neurons, correlating with higher activation of C/EBPß in human AD brains with ApoE4/4 compared to ApoE3/3. Therefore, our data support that C/EBPß is a crucial transcription factor for temporally regulating APOE gene expression, modulating ApoE4's role in AD pathogenesis.