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Abstract Background The global dementia prevalence is surging, necessitating research into contributing factors. We aimed to investigate the association between metabolic syndrome (MetS), its components, serum uric acid (SUA) levels, and dementia risk. Methods Our prospective study comprised 466,788 participants without pre-existing MetS from the UK Biobank. We confirmed dementia diagnoses based on the ICD-10 criteria (F00-03). To evaluate the dementia risk concerning MetS, its components, and SUA levels, we applied Cox proportional hazards models, while adjusting for demographic factors. Results Over a median follow-up of 12.7 years, we identified 6845 dementia cases. Individuals with MetS had a 25% higher risk of all-cause dementia (hazard ratio [HR] = 1.25, 95% confidence interval [CI] = 1.19–1.31). The risk increased with the number of MetS components including central obesity, dyslipidemia for high-density lipoprotein (HDL) cholesterol, hypertension, hyperglycemia, and dyslipidemia for triglycerides. Particularly for those with all five components (HR = 1.76, 95% CI = 1.51–2.04). Dyslipidemia for HDL cholesterol, hypertension, hyperglycemia, and dyslipidemia for triglycerides were independently associated with elevated dementia risk (p < 0.01). MetS was further linked to an increased risk of all-cause dementia (11%) and vascular dementia (VD, 50%) among individuals with SUA levels exceeding 400 μmol/L (all-cause dementia: HR = 1.11, 95% CI = 1.02–1.21; VD: HR = 1.50, 95% CI = 1.28–1.77). Conclusions Our study provides robust evidence supporting the association between MetS, its components, and dementia risk. These findings emphasize the importance of considering MetS and SUA levels in assessing dementia risk, offering valuable insights for prevention and management strategies.

Abstract Aquaporin-4 (AQP4) is essential for normal functioning of the brain’s glymphatic system. Impaired glymphatic function is associated with neuroinflammation. Recent clinical evidence suggests the involvement of glymphatic dysfunction in LRRK2-associated Parkinson’s disease (PD); however, the precise mechanism remains unclear. The pro-inflammatory cytokine interferon (IFN) γ interacts with LRRK2 to induce neuroinflammation. Therefore, we examined the AQP4-dependent glymphatic system’s role in IFNγ-mediated neuroinflammation in LRRK2-associated PD. We found that LRRK2 interacts with and phosphorylates AQP4 in vitro and in vivo. AQP4 phosphorylation by LRRK2 R1441G induced AQP4 depolarization and disrupted glymphatic IFNγ clearance. Exogeneous IFNγ significantly increased astrocyte expression of IFNγ receptor, amplified AQP4 depolarization, and exacerbated neuroinflammation in R1441G transgenic mice. Conversely, inhibiting LRRK2 restored AQP4 polarity, improved glymphatic function, and reduced IFNγ-mediated neuroinflammation and dopaminergic neurodegeneration. Our findings establish a link between LRRK2-mediated AQP4 phosphorylation and IFNγ-mediated neuroinflammation in LRRK2-associated PD, guiding the development of LRRK2 targeting therapy.

Abstract Microinfarcts are common among the elderly and patients with microinfarcts are more vulnerable to another stroke. However, the impact of microinfarcts on recurrent stroke has yet to be fully understood. The purpose of this study was to explore the negative effects of microinfarcts on recurrent stroke. To achieve this, two-photon laser was used to induce microinfarcts, while photothrombotic stroke was induced on the opposite side. The results showed that microinfarcts led to trained immunity in microglia, which worsened the pro-inflammatory response and ischemic injury in the secondary photothrombotic stroke. Additionally, the study clarified the role of NLRP3 in microglial nuclei, indicating that it interacts with the MLL1 complex through NACHT domain and increases H3K4 methylation, which suggests that NLRP3 is critical in the formation of innate immune memory caused by microinfarcts. Furthermore, the knockout of NLRP3 in microglia alleviated the trained immunity and reduced the harmful effects of microinfarcts on recurrent stroke. This study emphasizes the detrimental effect of trained immunity on recurrent stroke and highlights the critical role of NLRP3 in mediating the formation of this memory, which may offer a potential therapeutic target for mitigating recurrent strokes.

Abstract Advances in chimeric antigen receptor (CAR)-T cell therapy have significantly improved clinical outcomes of patients with relapsed or refractory hematologic malignancies. However, progress is still hindered as clinical benefit is only available for a fraction of patients. A lack of understanding of CAR-T cell behaviors in vivo at the single-cell level impedes their more extensive application in clinical practice. Mounting evidence suggests that single-cell sequencing techniques can help perfect the receptor design, guide gene-based T cell modification, and optimize the CAR-T manufacturing conditions, and all of them are essential for long-term immunosurveillance and more favorable clinical outcomes. The information generated by employing these methods also potentially informs our understanding of the numerous complex factors that dictate therapeutic efficacy and toxicities. In this review, we discuss the reasons why CAR-T immunotherapy fails in clinical practice and what this field has learned since the milestone of single-cell sequencing technologies. We further outline recent advances in the application of single-cell analyses in CAR-T immunotherapy. Specifically, we provide an overview of single-cell studies focusing on target antigens, CAR-transgene integration, and preclinical research and clinical applications, and then discuss how it will affect the future of CAR-T cell therapy.

Human RAB39B gene is related to familial early-onset Parkinson disease. In early adulthood, men with the RAB39B c.503C > A (Thr168Lys, p. T168K) mutation develop typical tremor, bradykinesia, and alpha-synuclein accumulation. We investigated the pathological mechanism of RAB39B T168K in a Caenorhabditis elegans model. In early adult C. elegans, RAB39B T168K led to dopaminergic neuron degeneration that presented as disrupted dendrites and blunt neuronal cells. Abnormal dopamine secretion was inferred from a decline in motor function and a positive basal slowing phenotype. Dopamine-associated tests confirmed that synthesis and recycling of dopamine were normal. The RAB39B T168K mutation might impair dopamine vesicular transmission from the presynaptic membrane to the synaptic gap in dopaminergic neurons. The release-dependent feedback mechanism in neurotransmitters regulates the balance of receptor activities. Protein-protein interactions network analysis revealed that RAB39B may also function in lysosomal degradation and autophagy. Impaired disposal of misfolded α-synuclein eventually leads to protein aggregation. Thus, like other members of the Rab family, RAB39B may be involved in vesicular transport associated with dopamine secretion and α-synuclein clearance.

Abstract Background Coronavirus disease 2019 (COVID‐19) may influence the clinical course and symptoms of chronic neurological diseases, such as Parkinson's disease (PD), which can persist even after recovery from the infection. This longitudinal study aimed at exploring the impact of the COVID‐19 on motor and non‐motor symptoms and the related risk factors for exacerbation of PD symptoms. Methods One hundred and two PD patients underwent a first assessment between September 2022 and November 2022 (T0) before Omicron COVID‐19 pandemic. They were then contacted again and asked to complete the second assessment between December 2022 and February 2023 (T1) following Omicron infection. Movement Disorders Society Unified PD Rating Scale Part III, Non‐Motor Symptoms Scale, Fatigue Severity Scale (FSS), and quality of life were investigated. Results Ninety‐five PD patients (93.1%) with COVID‐19 for the first time were mild cases. However, 55 patients (55.9%) experienced worsening motor symptoms of PD after recovering from the infectious symptoms. Preinfection FSS score (odds ratios [OR] 2.062, 95% confidence interval [CI] 1.081–3.933, p = .028) and duration of infection (OR 1.232, 95% CI 1.024–1.481, p = .027) were independent risk factors for the worsening of motor symptoms. PD patients with post‐COVID‐19 fatigue were more likely to experience worsened non‐motor symptoms, resulting in an impaired quality of life. Conclusion This study confirms the impact of the Omicron COVID‐19 pandemic on the motor and non‐motor symptoms of PD, suggesting that management of related factors, including fatigue and duration of infection, may be beneficial in preventing or dealing with the exacerbation of PD symptoms after infection.

Abstract Acute myeloid leukemia (AML) is a hematological malignancy characterized by the impaired differentiation and uncontrolled proliferation of myeloid blasts. Tumor suppressor p53 is often downregulated in AML cells via ubiquitination-mediated degradation. While the role of E3 ligase MDM2 in p53 ubiquitination is well-accepted, little is known about the involvement of deubiquitinases (DUBs). Herein, we found that the expression of YOD1, among several DUBs, is substantially reduced in blood cells from AML patients. We identified that YOD1 deubiqutinated and stabilized p53 through interaction via N-terminus of p53 and OTU domain of YOD1. In addition, expression levels of YOD1 were suppressed by elevated miR-221/222 in AML cells through binding to the 3′ untranslated region of YOD1, as verified by reporter gene assays. Treatment of cells with miR-221/222 mimics and inhibitors yielded the expected effects on YOD1 expressions, in agreement with the negative correlation observed between the expression levels of miR-221/222 and YOD1 in AML cells. Finally, overexpression of YOD1 stabilized p53, upregulated pro-apoptotic p53 downstream genes, and increased the sensitivity of AML cells to FLT3 inhibitors remarkably. Collectively, our study identified a pathway connecting miR-221/222, YOD1, and p53 in AML. Targeting miR-221/222 and stimulating YOD1 activity may improve the therapeutic effects of FLT3 inhibitors in patients with AML.

ObjectivesIn this review, we aim to highlight the evidence base for the benefits of exercise in relation to the treatment of noncommunicable diseases (NCDs), draw on the Health Triangular Policy Framework to outline the principal facilitators and barriers for implementing exercise in health policy, and make concrete suggestions for action.MethodsLiterature review and framework analysis were conducted to deal with the research questions.ResultsExercise prescription is a safe solution for noncommunicable diseases prevention and treatment that enables physicians to provide and instruct patients how to apply exercise as an important aspect of disease treatment and management. Combining exercise prescription within routine care, in inpatient and outpatient settings, will improve patients’ life quality and fitness levels.ConclusionInserting exercise prescription into the healthcare system would improve population health status and healthy lifestyles. The suggestions outlined in this study need combined efforts from the medical profession, governments, and policymakers to facilitate practice into reality in the healthcare arena.

Abstract Background Periodontitis is closely associated with the pathogenesis of Alzheimer’s disease (AD). Porphyromonas gingivalis (Pg), the keystone periodontal pathogen, has been reported in our recent study to cause immune-overreaction and induce cognitive impairment. Monocytic myeloid-derived suppressor cells (mMDSCs) possess potent immunosuppressive function. It is unclear whether mMDSCs-mediated immune homeostasis is impaired in AD patients with periodontitis, and whether exogenous mMDSCs could ameliorate immune-overreaction and cognitive impairment induced by Pg. Methods To explore the influence of Pg on cognitive function, neuropathology and immune balance in vivo, 5xFAD mice were treated with live Pg by oral gavage, three times a week for 1 month. The cells of peripheral blood, spleen and bone marrow from 5xFAD mice were treated with Pg to detect the proportional and functional alterations of mMDSCs in vitro. Next, exogenous mMDSCs were sorted from wild-type healthy mice and intravenously injected into 5xFAD mice that were infected with Pg. We used behavioral tests, flow cytometry and immunofluorescent staining to evaluate whether exogenous mMDSCs could ameliorate the cognitive function, immune homeostasis and reduce neuropathology exacerbated by Pg infection. Results Pg exacerbated cognitive impairment in 5xFAD mice, with the deposition of amyloid plaque and increased number of microglia in the hippocampus and cortex region. The proportion of mMDSCs decreased in Pg-treated mice. In addition, Pg reduced the proportion and the immunosuppressive function of mMDSCs in vitro. Supplement of exogenous mMDSCs improved the cognitive function, and enhanced the proportions of mMDSCs and IL-10+ T cells of 5xFAD mice infected with Pg. At the same time, supplement of exogenous mMDSCs increased the immunosuppressive function of endogenous mMDSCs while decreased the proportions of IL-6+ T cells and IFN-γ+ CD4+ T cells. In addition, the deposition of amyloid plaque decreased while the number of neurons increased in the hippocampus and cortex region after the supplement of exogenous mMDSCs. Furthermore, the number of microglia increased with an increase in the proportion of M2 phenotype. Conclusions Pg can reduce the proportion of mMDSCs, induce immune-overreaction, and exacerbate the neuroinflammation and cognitive impairment in 5xFAD mice. Supplement of exogenous mMDSCs can reduce the neuroinflammation, immune imbalance and cognitive impairment in 5xFAD mice infected with Pg. These findings indicate the mechanism of AD pathogenesis and Pg-mediated promotion of AD, and provide a potential therapeutic strategy for AD patients.

This article introduces a high-throughput molecular screening chip： peptide arrays. As a kind of biochip， the peptide arrays are easy to synthesis， stable in probe chemistry， high-throughput in screening and highly specific compared with other biochips. To analyze the new high-throughput data， researchers have recently proposed a series of deep learning and bioinformatics methods to study the binding characteristics of peptide probes and target molecules. Those algorithms could be used to predict the binding affinity of protein targets against peptides. Moreover， peptide arrays could also play important roles in analyzing protein-protein interactions，screening novel drug peptides， disease diagnosis and general health assessment based on recent reports. The application of this new technology could provide novel insights into public health research.

BackgroundFrailty is a dynamic and complex geriatric condition characterized by multi-domain declines in physiological, gait and cognitive function. This study examined whether digital health technology can facilitate frailty identification and improve the efficiency of diagnosis by optimizing analytical and machine learning approaches using select factors from comprehensive geriatric assessment and gait characteristics.MethodsAs part of an ongoing study on observational study of Aging, we prospectively recruited 214 individuals living independently in the community of Southern China. Clinical information and fragility were assessed using comprehensive geriatric assessment (CGA). Digital tool box consisted of wearable sensor-enabled 6-min walk test (6MWT) and five machine learning algorithms allowing feature selections and frailty classifications.ResultsIt was found that a model combining CGA and gait parameters was successful in predicting frailty. The combination of these features in a machine learning model performed better than using either CGA or gait parameters alone, with an area under the curve of 0.93. The performance of the machine learning models improved by 4.3–11.4% after further feature selection using a smaller subset of 16 variables. SHapley Additive exPlanation (SHAP) dependence plot analysis revealed that the most important features for predicting frailty were large-step walking speed, average step size, age, total step walking distance, and Mini Mental State Examination score.ConclusionThis study provides evidence that digital health technology can be used for predicting frailty and identifying the key gait parameters in targeted health assessments.

Background:. Parkinson's disease (PD) is the second most common neurodegenerative disease after Alzheimer's dementia. Mitochondrial dysfunction is involved in the pathology of PD. Coiled-coil-helix-coiled-coil-helix domain-containing 2 (CHCHD2) was identified as associated with autosomal dominant PD. However, the mechanism of CHCHD2 in PD remains unclear. Methods:. Short hairpin RNA (ShRNA)-mediated CHCHD2 knockdown or lentivirus-mediated CHCHD2 overexpression was performed to investigate the impact of CHCHD2 on mitochondrial morphology and function in neuronal tumor cell lines represented with human neuroblastoma (SHSY5Y) and HeLa cells. Blue-native polyacrylamide gel electrophoresis (PAGE) and two-dimensional sodium dodecyl sulfate-PAGE analysis were used to illustrate the role of CHCHD2 in mitochondrial contact site and cristae organizing system (MICOS). Co-immunoprecipitation and immunoblotting were used to address the interaction between CHCHD2 and Mic10. Serotype injection of adeno-associated vector-mediated CHCHD2 and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administration were used to examine the influence of CHCHD2 in vivo. Results:. We found that the overexpression of CHCHD2 can protect against methyl-4-phenylpyridinium (MPP+)-induced mitochondrial dysfunction and inhibit the loss of dopaminergic neurons in the MPTP-induced mouse model. Furthermore, we identified that CHCHD2 interacted with Mic10, and overexpression of CHCHD2 can protect against MPP+-induced MICOS impairment, while knockdown of CHCHD2 impaired the stability of MICOS. Conclusion:. This study indicated that CHCHD2 could interact with Mic10 and maintain the stability of the MICOS complex, which contributes to protecting mitochondrial function in PD.

Ribosome RNA (rRNA) accounts for more than 80% of the cell's total RNA, while the physiological functions of rRNA modifications are poorly understood. Mutations of 18S rRNA m6A methyltransferase METTL5 cause intellectual disability, microcephaly, and facial dysmorphisms in patients, however, little is known about the underlying mechanisms. In this study, we identified METTL5 protein complex and revealed that METTL5 mainly interacts with RNA binding proteins and ribosome proteins. Functionally, we found that Mettl5 knockout in mESCs leads to the abnormal craniofacial and nervous development. Moreover, using Mettl5 knockout mouse model, we further demonstrated that Mettl5 knockout mice exhibit intellectual disability, recapitulating the human phenotype. Mechanistically, we found that Mettl5 maintains brain function and intelligence by regulating the myelination process. Our study uncovered the causal correlation between mis-regulated 18S rRNA m6A modification and neural function defects, supporting the important physiological functions of rRNA modifications in human diseases.

Nitrogen (N) deep placement has been found to reduce N leaching and increase N use efficiency in paddy fields. However, relatively little is known how bacterial consortia, especially abundant and rare taxa, respond to N deep placement, which is critical for understanding the biodiversity and function of agricultural ecosystem. In this study, Illumina sequencing and ecological models were conducted to examine the diversity patterns and underlying assembly mechanisms of abundant and rare taxa in rice rhizosphere soil under different N fertilization regimes at four rice growth stages in paddy fields. The results showed that abundant and rare bacteria had distinct distribution patterns in rhizosphere samples. Abundant bacteria showed ubiquitous distribution; while rare taxa exhibited uneven distribution across all samples. Stochastic processes dominated community assembly of both abundant and rare bacteria, with dispersal limitation playing a more vital role in abundant bacteria, and undominated processes playing a more important role in rare bacteria. The N deep placement was associated with a greater influence of dispersal limitation than the broadcast N fertilizer (BN) and no N fertilizer (NN) treatments in abundant and rare taxa of rhizosphere soil; while greater contributions from homogenizing dispersal were observed for BN and NN in rare taxa. Network analysis indicated that abundant taxa with closer relationships were usually more likely to occupy the central position of the network than rare taxa. Nevertheless, most of the keystone species were rare taxa and might have played essential roles in maintaining the network stability. Overall, these findings highlighted that the ecological mechanisms and co-occurrence patterns of abundant and rare bacteria in rhizosphere soil under N deep placement.

Parent materials and the fertility levels of paddy soils are highly variable in subtropical China. Bacterial diversity and community composition play pivotal roles in soil ecosystem processes and functions. However, the effects of parent material and fertility on bacterial diversity and community composition in paddy soils are unclear. The key soil factors driving the changes in bacterial diversity, community composition, and the specific bacterial species in soils that are derived from different parent materials and have differing fertility levels are unknown. Soil samples were collected from paddy fields in two areas with different parent materials (quaternary red clay or tertiary sandstone) and two levels of fertility (high or low). The variations in bacterial diversity indices and communities were evaluated by 454 pyrosequencing which targeted the V4–V5 region of the 16S rRNA gene. The effects of parent material and fertility on bacterial diversity and community composition were clarified by a two-way ANOVA and a two-way PERMANOVA. A principal coordinate analysis (PCoA), a redundancy analysis (RDA), and multivariate regression trees (MRT) were used to assess changes in the studied variables and identify the factors affecting bacterial community composition. Co-occurrence network analysis was performed to find correlations between bacterial genera and specific soil properties, and a statistical analysis of metagenomic profiles (STAMP) was used to determine bacterial genus abundance differences between the soil samples. The contributions made by parent material and soil fertility to changes in the bacterial diversity indices were comparable, but soil fertility accounted for a larger part of the shift in bacterial community composition than the parent material. Soil properties, especially soil texture, were strongly associated with bacterial diversity. The RDA showed that soil organic carbon (SOC) was the primary factor influencing bacterial community composition. A key threshold for SOC (25.5 g kg–1) separated low fertility soils from high fertility soils. The network analysis implied that bacterial interactions tended towards cooperation and that copiotrophic bacteria became dominant when the soil environment improved. The STAMP revealed that copiotrophic bacteria, such as Massilia and Rhodanobacter, were more abundant in the high fertility soils, while oligotrophic bacteria, such as Anaerolinea, were dominant in low fertility soils. The results showed that soil texture played a role in bacterial diversity, but nutrients, especially SOC, shaped bacterial community composition in paddy soils with different parent materials and fertility levels.

Abstract Background Neuroinflammation is a major driver of age-related brain degeneration and concomitant functional impairment. In patients with Alzheimer’s disease, the most common form of age-related dementia, factors that enhance neuroinflammation may exacerbate disease progression, in part by impairing the glymphatic system responsible for clearance of pathogenic beta-amyloid. Inflammatory bowel diseases (IBDs) induce neuroinflammation and exacerbate cognitive impairment in the elderly. The NACHT-LRR and pyrin (PYD) domain-containing protein 3 (NLRP3) inflammasome has been implicated in neuroinflammation. Therefore, we examined if the NLRP3 inflammasome contributes to glymphatic dysfunction and cognitive impairment in an aging mouse model of IBD. Methods Sixteen-month-old C57BL/6J and NLRP3 knockout (KO) mice received 1% wt/vol dextran sodium sulfate (DSS) in drinking water to model IBD. Colitis induction was confirmed by histopathology. Exploratory behavior was examined in the open field, associative memory by the novel-object recognition and Morris water maze tests, glymphatic clearance by in vivo two-photon imaging, and neuroinflammation by immunofluorescence and western blotting detection of inflammatory markers. Results Administration of DSS induced colitis, impaired spatial and recognition memory, activated microglia, and increased A1-like astrocyte numbers. In addition, DSS treatment impaired glymphatic clearance, aggravated amyloid plaque accumulation, and induced neuronal loss in the cortex and hippocampus. These neurodegenerative responses were associated with increased NLRP3 inflammasome expression and accumulation of gut-derived T lymphocytes along meningeal lymphatic vessels. Conversely, NLRP3 depletion protected against cognitive dysfunction, neuroinflammation, and neurological damage induced by DSS. Conclusions Colitis can exacerbate age-related neuropathology, while suppression of NLRP3 inflammasome activity may protect against these deleterious effects of colitis.

Objectives There is significant burden on caregivers of patients with amyotrophic lateral sclerosis (ALS). However, only a few studies have focused on caregivers, and traditional research methods have obvious shortcomings in dealing with multiple influencing factors. This study was designed to explore influencing factors on caregiver burden among ALS patients and their caregivers from a new perspective.Design Cross-sectional study.Setting The data were collected at an affiliated hospital in Guangzhou, Guangdong, China.Participants Fifty-seven pairs of patients with ALS and their caregivers were investigated by standardised questionnaires.Main outcome measures This study primarily assessed the influencing factor of caregiver burden including age, gender, education level, economic status, anxiety, depression, social support, fatigue, sleep quality and stage of disease through data mining. Statistical analysis was performed using SPSS 24.0, and least absolute shrinkage and selection operator (LASSO) regression model was established by Python 3.8.1 to minimise the effect of multicollinearity.Results According to LASSO regression model, we found 10 variables had weights. Among them, Milano-Torinos (MITOS) stage (0–1) had the highest weight (−12.235), followed by younger age group (−3.198), lower-educated group (2.136), fatigue (1.687) and social support (-0.455). Variables including sleep quality, anxiety, depression and sex (male) had moderate weights in this model. Economic status (common), economic status (better), household (city), household (village), educational level (high), sex (female), age (older) and MITOS stage (2–4) had a weight of zero.Conclusions Our study demonstrates that the severity of ALS patients is the most influencing factor in caregiver burden. Caregivers of ALS patients may suffer less from caregiver burden when the patients are less severe, and the caregivers are younger. Low educational status could increase caregiver burden. Caregiver burden is positively correlated with the degree of fatigue and negatively correlated with social support. Hopefully, more attention should be paid to caregivers of ALS, and effective interventions can be developed to relieve this burden.

Gain-of-function mutations of isocitrate dehydrogenases 1/2 (IDH1/2) play crucial roles in the development and progression of acute myeloid leukemia (AML), which provide promising therapeutic targets. Two small molecular inhibitors, ivosidenib and enasidenib have been approved for the treatment of IDH1- and IDH2-mutant AML, respectively. Although these inhibitors benefit patients with AML clinically, drug resistance still occurs and have become a major problem for targeted therapies of IDH-mutant AML. A number of up-to-date studies have demonstrated molecular mechanisms of resistance, providing rationales of novel therapeutic strategies targeting mutant IDH1/2. In this review, we discuss mechanisms of resistance to ivosidenib and enasidenib in patients with AML.

Cerebral small-vessel disease (CSVD) is the main cause of vascular cognitive impairment (VCI), and the accumulation of amyloid β-protein (Aβ) may be significantly involved in CSVD-induced VCI. The imbalance between Aβ production and clearance is believed to be an important pathological mechanism of Aβ deposition in Alzheimer disease. In this study, we aimed to disclose the roles of aquaporin 4 (AQP4) and neuroinflammation in CSVD, which were the key factors for Aβ clearance and production, respectively, and the effect of mesenchymal stem cells (MSCs) on Aβ deposition and these two factors. The stroke-prone renovascular hypertensive (RHRSP) rats were grouped and received MSC and MSC + AS1517499 (an inhibitor of pSTAT6). The latter was used to explore the underlying mechanism. The cognitive function, white matter lesions, Aβ expression, expression, and polarity of AQP4, neuroinflammation and the STAT6 pathway were investigated. Compared with sham-operated rats, RHRSP rats showed spatial cognitive impairment, white matter lesions and Aβ deposition. Moreover, AQP4 polarity disorder and neuroinflammatory activation were found, which were linked to Aβ deposition. Treatment with MSCs markedly improved cognitive tasks and reduced Aβ deposition but failed to reduce white-matter lesions. Furthermore, MSCs not only promoted AQP4 polarity but also alleviated neuroinflammation probably through the STAT6 pathway. The present study demonstrated that Aβ deposition, AQP4 polarity disorder and neuroinflammation might be involved in CSVD and the regulatory effects of MSCs on them suggested potential therapeutic value for CSVD.