CHIT1-positive microglia drive motor neuron ageing in the primate spinal cord.

Ageing is a critical factor in spinal-cord-associated disorders1, yet the ageing-specific mechanisms underlying this relationship remain poorly understood. Here, to address this knowledge gap, we combined single-nucleus RNA-sequencing analysis with behavioural and neurophysiological analysis in non-human primates (NHPs). We identified motor neuron senescence and neuroinflammation with microglial hyperactivation as intertwined hallmarks of spinal cord ageing. As an underlying mechanism, we identified a neurotoxic microglial state demarcated by elevated expression of CHIT1 (a secreted mammalian chitinase) specific to the aged spinal cords in NHP and human biopsies. In the aged spinal cord, CHIT1-positive microglia preferentially localize around motor neurons, and they have the ability to trigger senescence, partly by activating SMAD signalling. We further validated the driving role of secreted CHIT1 on MN senescence using multimodal experiments both in vivo, using the NHP spinal cord as a model, and in vitro, using a sophisticated system modelling the human motor-neuron-microenvironment interplay. Moreover, we demonstrated that ascorbic acid, a geroprotective compound, counteracted the pro-senescent effect of CHIT1 and mitigated motor neuron senescence in aged monkeys. Our findings provide the single-cell resolution cellular and molecular landscape of the aged primate spinal cord and identify a new biomarker and intervention target for spinal cord degeneration.

An artificial intelligence-enabled electrocardiogram algorithm for the prediction of left atrial low-voltage areas in persistent atrial fibrillation.

OBJECTIVES: We aimed to construct an artificial intelligence-enabled electrocardiogram (ECG) algorithm that can accurately predict the presence of left atrial low-voltage areas (LVAs) in patients with persistent atrial fibrillation. METHODS: The study included 587 patients with persistent atrial fibrillation who underwent catheter ablation procedures between March 2012 and December 2023 and 942 scanned images of 12-lead ECGs obtained before the ablation procedures were performed. Artificial intelligence-based algorithms were used to construct models for predicting the presence of LVAs. The DR-FLASH and APPLE clinical scores for LVA prediction were calculated. We used a receiver operating characteristic (ROC) curve, calibration curve, and decision curve analysis to evaluate model performance. RESULTS: The data obtained from the participants were split into training (n = 469), validation (n = 58), and test sets (n = 60). LVAs were detected in 53.7% of all participants. Using ECG alone, the deep learning algorithm achieved an area under the ROC curve (AUROC) of 0.752, outperforming both the DR-FLASH score (AUROC = 0.610) and the APPLE score (AUROC = 0.510). The random forest classification model, which integrated a probabilistic deep learning model and clinical features, showed a maximum AUROC of 0.759. Moreover, the ECG-based deep learning algorithm for predicting extensive LVAs achieved an AUROC of 0.775, with a sensitivity of 0.816 and a specificity of 0.896. The random forest classification model for predicting extensive LVAs achieved an AUROC of 0.897, with a sensitivity of 0.862, and a specificity of 0.935. CONCLUSION: The deep learning model based exclusively on ECG data and the machine learning model that combined a probabilistic deep learning model and clinical features both predicted the presence of LVAs with a higher degree of accuracy than the DR-FLASH and the APPLE risk scores.

Cationic Hypervalent Chalcogen Bond Catalysis on the Povarov Reaction: Reactivity and Stereoselectivity.

Chalcogen bond catalysis, particularly cationic hypervalent chalcogen bond catalysis, is considered to be an effective strategy for organocatalysis. In this work, the cationic hypervalent chalcogen bond catalysis for the Povarov reaction between N-benzylideneaniline and ethyl vinyl ether was investigated by density functional theory (DFT). The catalytic reaction involves the cycloaddition process and the proton transfer process, and the rate-determining step is the cycloaddition process. Cationic hypervalent tellurium derivatives bearing CF3 and F groups exhibit superior catalytic activity. For the rate-determining step, the Gibbs free energy barrier decreases as the positive electrostatic potential of the chalcogen bond catalysts increases. More importantly, the Gibbs free energy barrier has a strong linear correlation with the electrostatic energy of the chalcogen bond in the catalyst-substrate complex. Furthermore, the catalytic reactions include the endo pathway and exo pathway. The C-H⋅⋅⋅π interaction between the substituent of the ethyl vinyl ether and the aryl ring of the N-benzylideneaniline contributes to the endo-selectivity of the reaction. This research contributes to a deeper understanding of chalcogen bond catalysis, providing insights for designing chalcogen bond catalysts with high performance.

Clarity on the blazing trail: clearing the way for amyloid-removing therapies for Alzheimer's disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder with a complex pathogenesis. Senile plaques composed of the amyloid-ß (Aß) peptide in the brain are the core hallmarks of AD and a promising target for the development of disease-modifying therapies. However, over the past 20 years, the failures of clinical trials directed at Aß clearance have fueled a debate as to whether Aß is the principal pathogenic factor in AD and a valid therapeutic target. The success of the recent phase 3 trials of lecanemab (Clarity AD) and donanemab (Trailblazer Alz2), and lessons from previous Aß clearance trials provide critical evidence to support the role of Aß in AD pathogenesis and suggest that targeting Aß clearance is heading in the right direction for AD treatment. Here, we analyze key questions relating to the efficacy of Aß targeting therapies, and provide perspectives on early intervention, adequate Aß removal, sufficient treatment period, and combinatory therapeutics, which may be required to achieve the best cognitive benefits in future trials in the real world.

Preoperative and intraoperative tirofiban during endovascular thrombectomy in large vessel occlusion stroke due to large artery atherosclerosis.

BACKGROUND AND PURPOSE: The aim of this study is to investigate the efficacy and safety of preoperative versus intraoperative tirofiban in patients with large vessel occlusion (LVO) due to large artery atherosclerosis (LAA). METHODS: This is a retrospective multicenter cohort study based on the RESCUE-RE (Registration Study for Critical Care of Acute Ischemic Stroke After Recanalization) trial enrolling patients with anterior circulation LVO classified as LAA within 24 h of onset. Patients were divided into three groups: preoperative tirofiban (PT), intraoperative tirofiban (IT), and no tirofiban (NT). Propensity score matching (PSM) was used to balance baseline characteristics. The efficacy outcomes included 90-day functional independence (modified Rankin Scale score = 0-2) and early partial recanalization (EPR; defined as a modified Thrombolysis in Cerebral Infarction score = 1-2a). The safety outcomes included symptomatic intracranial hemorrhage (sICH). RESULTS: A total of 104 matched triplets were obtained through PSM. Compared with NT, PT increased 90-day functional independence (60.8% vs. 42.3%, p = 0.008) and EPR (42.7% vs. 18.3%, p < 0.001) rate, with a tendency to increase the asymptomatic intracranial hemorrhage (aICH) proportion (28.8% vs. 18.3%, p = 0.072). Compared with IT, PT had a higher 90-day functional independence (60.8% vs. 45.2%, p = 0.025) and EPR (42.7% vs. 20.2%, p = 0.001) rate, with no significant difference in sICH (14.4% vs. 7.7%, p = 0.122) and aICH (28.8% vs. 21.2%, p = 0.200). Compared with NT, IT had a lower 90-day mortality rate (9.6% vs. 24.0%, p = 0.005). CONCLUSIONS: Tirofiban shows good adjuvant therapy potential in acute ischemic stroke-LVO due to LAA patients. PT is associated with higher rates of EPR and better therapeutic efficacy. In addition, EPR may be a potential way to improve prognosis.

99mTc-HFAPi SPECT imaging predicts left ventricular remodeling after acute myocardial infarction.

BACKGROUND: Despite improved treatments for acute myocardial infarction (AMI), myocardial fibrosis remains a key driver of adverse left ventricular (LV) remodeling and increased mortality. Fibroblast activation and proliferation significantly contribute to this process by enhancing cardiac fibrosis, which can lead to detrimental changes in LV structure. This study evaluates the effectiveness of 99mTc-labeled fibroblast activation protein inhibitor (99mTc-HFAPi) SPECT imaging in predicting LV remodeling over 12 months in post-AMI patients. METHODS: A cohort of 58 AMI patients (46 males, median age 61 [53, 67] years) underwent baseline 99mTc-HFAPi imaging (5 ± 2 days post-MI), perfusion imaging (6 ± 2 days post-MI), and echocardiography (2 ± 2 days post-MI). Additionally, 15 patients had follow-up 99mTc-HFAPi and perfusion imaging, while 30 patients had follow-up echocardiography. Myocardial 99mTc-HFAPi activity was assessed at the patient level. LV remodeling was defined as a ≥10% increase in LV end-diastolic diameter (LVEDD) or LV end-systolic diameter (LVESD) from baseline to follow-up echocardiography. RESULTS: AMI patients displayed localized but non-uniform 99mTc-HFAPi uptake, exceeding perfusion defects. Baseline 99mTc-HFAPi activity exhibited significant correlations with BNPmax, LDHmax, cTNImax, and WBCmax, inversely correlating with LVEF. After 12 months, 11 patients (36.66%) experienced LV remodeling. Univariate regression analysis demonstrated an association between baseline 99mTc-HFAPi uptake extent and LV remodeling (OR = 2.14, 95%CI, 1.04, 4.39, P = 0.038). CONCLUSIONS: 99mTc-HFAPi SPECT imaging holds promise in predicting LV remodeling post-MI, providing valuable insights for patient management and prognosis.

Impact of Pulsed Electric Field Ablation on His Bundle Conduction: A Preclinical Canine Study.

BACKGROUND Pulsed field ablation (PFA), as a non-thermal ablation modality, has received increasing attention. The aim of this study was to evaluate the effect of PFA upon His bundle via its implementation with different voltages on the maximum His bundle potential in canines, providing scientific basis for clinical application. MATERIAL AND METHODS Pulsed electrical field energy was delivered from a ablation catheter to the maximum His potential of 7 dogs, followed by a series of electrogram and histology assessments. RESULTS The baseline AH and HV intervals were 55.3±3.7 ms (range, 53.0-59.0 ms), and 34.9±1.3 ms (range, 34.0-36.0 ms), respectively, which were elevated to 65.0±5.4 ms (range, 59.0-70.0 ms) and 35.7±2.7 ms (range, 34.0-37.0 ms) after PFA. Before ablation and immediately after the recovery of third-degree AVB, the AH interval was prolonged (P<0.05) while the HV interval remained unchanged (P>0.05). After ablation, all 7 canines experienced transient third-degree AVB, with a voltage-dependent duration. Masson staining results revealed no apparent damage in His bundle cells. CONCLUSIONS Within a certain voltage range of pulse electric field, ablation of the maximum His potential in canines can result in transient third-degree AVB, providing a new route for guiding safe ablation of para-Hisian arrhythmia.

Association of air pollutants with psychiatric disorders: a two-sample Mendelian randomization.

BACKGROUND: The link between air pollution and increased risk of psychiatric disorders has been growing in evidence. However, the causal relationship between air pollution and psychiatric disorders remains poorly understood. METHODS: Single-nucleotide polymorphisms associated with air pollutants (including NOx, NO2, PM2.5, PM2.5-10, and PM10) from the UK Biobank were used as instrumental variables. Summary-level data for psychiatric disorders (major depressive disorder, anxiety, bipolar disorder, schizophrenia, post-traumatic stress disorder, attention deficit hyperactivity disorder, autism spectrum disorder, anorexia nervosa, and obsessive-compulsive disorder) were procured from the Psychiatric Genomics Consortium and FinnGen consortium. Two-sample Mendelian randomization (MR) analysis was conducted to analyze the causal associations. RESULTS: The MR analysis revealed significant associations between certain air pollutants and specific types of psychiatric disorders. The inverse-variance weighted model of preliminary analysis indicated that genetically predicted NO2 was associated with increased risks of major depressive disorder (odds ratio [OR]: 1.13, 95 % confidence intervals [CI]: 1.00-1.28, P = 0.041), bipolar disorder (OR: 1.26, 95 % CI: 1.00-1.58, P = 0.0497), schizophrenia (OR: 1.57, 95 % CI: 1.23-2.00, P < 0.001), attention deficit hyperactivity disorder (OR: 1.61, 95 % CI: 1.25-2.09, P < 0.001) and autism spectrum disorder (OR: 1.39, 95 % CI: 1.01-1.91, P = 0.044). Genetically predicted PM2.5 showed a positive association with the risk of major depressive disorder (OR: 1.21, 95 % CI: 1.06-1.39, P = 0.006), bipolar disorder (OR: 1.32, 95 % CI: 1.03-1.69, P = 0.030) and attention deficit hyperactivity disorder (OR: 1.57, 95 % CI: 1.16-2.12, P = 0.004). In addition, our results also indicated that NOx (OR: 1.64, 95 % CI: 1.21-2.21, P = 0.0012) and PM10 (OR: 1.70, 95 % CI: 1.23-2.36, P = 0.0014) could increase the risk of attention deficit hyperactivity disorder. CONCLUSIONS: The MR analysis provides evidence for the causality of different air pollutants on specific psychiatric disorders, underscoring the importance of mitigating air pollution to reduce the risk of psychiatric disorders.

Crosstalk between bone and brain in Alzheimer's disease: Mechanisms, applications, and perspectives.

Alzheimer's disease (AD) is a neurodegenerative disease that involves multiple systems in the body. Numerous recent studies have revealed bidirectional crosstalk between the brain and bone, but the interaction between bone and brain in AD remains unclear. In this review, we summarize human studies of the association between bone and brain and provide an overview of their interactions and the underlying mechanisms in AD. We review the effects of AD on bone from the aspects of AD pathogenic proteins, AD risk genes, neurohormones, neuropeptides, neurotransmitters, brain-derived extracellular vesicles (EVs), and the autonomic nervous system. Correspondingly, we elucidate the underlying mechanisms of the involvement of bone in the pathogenesis of AD, including bone-derived hormones, bone marrow-derived cells, bone-derived EVs, and inflammation. On the basis of the crosstalk between bone and the brain, we propose potential strategies for the management of AD with the hope of offering novel perspectives on its prevention and treatment. HIGHLIGHTS: The pathogenesis of AD, along with its consequent changes in the brain, may involve disturbing bone homeostasis. Degenerative bone disorders may influence the progression of AD through a series of pathophysiological mechanisms. Therefore, relevant bone intervention strategies may be beneficial for the comprehensive management of AD.

Genome-wide meta-analysis identifies ancestry-specific loci for Alzheimer's disease.

INTRODUCTION: Alzheimer's disease (AD) is a devastating neurological disease with complex genetic etiology. Yet most known loci have only identified from the late-onset type AD in populations of European ancestry. METHODS: We performed a two-stage genome-wide association study (GWAS) of AD totaling 6878 Chinese and 63,926 European individuals. RESULTS: In addition to the apolipoprotein E (APOE) locus, our GWAS of two independent Chinese samples uncovered three novel AD susceptibility loci (KIAA2013, SLC52A3, and TCN2) and a novel ancestry-specific variant within EGFR (rs1815157). More replicated variants were observed in the Chinese (31%) than in the European samples (15%). In combining genome-wide associations and functional annotations, EGFR and TCN2 were prioritized as two of the most biologically significant genes. Phenome-wide Mendelian randomization suggests that high mean corpuscular hemoglobin concentration might protect against AD. DISCUSSION: The current study reveals novel AD susceptibility loci, emphasizes the importance of diverse populations in AD genetic research, and advances our understanding of disease etiology. HIGHLIGHTS: Loci KIAA2013, SLC52A3, and TCN2 were associated with Alzheimer's disease (AD) in Chinese populations. rs1815157 within the EGFR locus was associated with AD in Chinese populations. The genetic architecture of AD varied between Chinese and European populations. EGFR and TCN2 were prioritized as two of the most biologically significant genes. High mean corpuscular hemoglobin concentrations might have protective effects against AD.

Physiological ß-amyloid clearance by the liver and its therapeutic potential for Alzheimer's disease.

Cerebral amyloid-ß (Aß) accumulation due to impaired Aß clearance is a pivotal event in the pathogenesis of Alzheimer's disease (AD). Considerable brain-derived Aß is cleared via transporting to the periphery. The liver is the largest organ responsible for the clearance of metabolites in the periphery. Whether the liver physiologically clears circulating Aß and its therapeutic potential for AD remains unclear. Here, we found that about 13.9% of Aß42 and 8.9% of Aß40 were removed from the blood when flowing through the liver, and this capacity was decreased with Aß receptor LRP-1 expression down-regulated in hepatocytes in the aged animals. Partial blockage of hepatic blood flow increased Aß levels in both blood and brain interstitial fluid. The chronic decline in hepatic Aß clearance via LRP-1 knockdown specific in hepatocytes aggravated cerebral Aß burden and cognitive deficits, while enhancing hepatic Aß clearance via LRP-1 overexpression attenuated cerebral Aß deposition and cognitive impairments in APP/PS1 mice. Our findings demonstrate that the liver physiologically clears blood Aß and regulates brain Aß levels, suggesting that a decline of hepatic Aß clearance during aging could be involved in AD development, and hepatic Aß clearance is a novel therapeutic approach for AD.

Chalcogen Bond Catalysis with Telluronium Cations for Bromination Reaction: Importance of Electrostatic and Polarization Effects.

Recently, chalcogen bond catalysts with telluronium cations have garnered considerable attention in organic reactions. In this work, chalcogen bond catalysis on the bromination reaction of anisole with N-bromosuccinimide (NBS) with the telluronium cationic catalysts has been explored with density functional theory (DFT). The catalytic reaction is divided into two stages: the bromine transfer step and the proton transfer step. Based on the computational results, one can find the rate-determining step is the bromine transfer step. Moreover, the present study elucidates that a stronger chalcogen bond between catalysts and NBS will give better catalytic performance. Additionally, this work also clarified the importance of the electrostatic and polarization effects in the chalcogen bond between the oxygen atom of NBS and the Te atom of the catalyst in this bromination reaction. The electrostatic and polarization effects are significantly influenced by the electron-withdrawing ability of the substitution groups on the catalysts. Moreover, the structure-property relationship between the strength of chalcogen bond, electrostatic effect, polarization effect and catalytic performance are established for the design of more efficient chalcogen bond catalysts.

Time-dependent impact of type 2 diabetes mellitus on incident prodromal Alzheimer disease: A longitudinal study in 1395 participants.

BACKGROUND AND PURPOSE: This study was undertaken to investigate the longitudinal impact of type 2 diabetes mellitus (T2DM) on the prodromal and dementia stages of Alzheimer disease (AD), focusing on diabetes duration and other comorbidities. METHODS: A total of 1395 dementia-free individuals aged 55-90 years with maximum 15-year follow-up data were enrolled from the Alzheimer's Disease Neuroimaging Initiative database. Cox proportional hazards regression models were used to estimate hazard ratios (HRs) of the incidence of prodromal or dementia stages of AD. RESULTS: Longer T2DM duration (≥5 years; multiadjusted HR = 2.19, 95% confidence interval [CI] = 1.05-4.58), but not shorter T2DM duration (<5 years), was associated with a significantly increased risk of incident prodromal AD over a mean follow-up of 4.8 years. APOE ε4 allele (HR = 3.32, 95% CI = 1.41-7.79) and comorbid coronary artery disease (CAD; HR = 3.20, 95% CI = 1.29-7.95) further increased the risk of incident prodromal AD in patients with T2DM. No significant association was observed between T2DM and the risk of progression from prodromal AD to AD dementia. CONCLUSIONS: T2DM, which is characterized by a longer duration, increases the incidence risk of prodromal AD but not AD dementia. APOE ε4 allele and comorbid CAD strengthen the relationship between T2DM and prodromal AD. These findings highlight T2DM characteristics and its comorbidities as predictors for accurate prediction of AD and screening of at-risk populations.

Fibroblast activation protein imaging in atrial fibrillation: a proof-of-concept study.

BACKGROUND: To evaluate the feasibility of using radiolabeled fibroblast activation protein inhibitor (FAPI) PET/CT imaging to assess activated fibroblasts in the atria of individuals with AF and to identify factors contributing to enhanced atrial activity. METHODS: We constructed left atrial appendage (LAA) pacing beagle dog AF models (n = 5) and conducted 18F-FAPI PET/CT imaging at baseline and eight weeks after pacing. Right atrial (RA) specimens were collected from these models. Additionally, 28 AF patients and ten age- and sex-matched healthy volunteers underwent 18F-FAPI PET/CT imaging. RESULTS: RA of AF beagles showed increased 18F-FAPI uptake. Among AF patients, 18 out of 28 (64.3%) exhibited enhanced atrial FAPI activity. No atrial 18F-FAPI uptake was observed in the sham beagle and healthy volunteers. In animal RA specimens, 18F-FAPI activity correlated positively with FAP mRNA (r = .98, P = .002) and protein (r = .82, P = .03) levels, as well as collagen I mRNA expression (r = .85, P = .02). B-type natriuretic peptide levels were associated with atrial 18F-FAPI activity (OR = 3.01, P = .046). CONCLUSION: This proof-of-concept study suggests that 18F-FAPI PET/CT imaging may be a feasible method for evaluating activated fibroblasts in the atria of AF patients.

Translating blood biomarkers into clinical practice for Alzheimer's disease: Challenges and perspectives.

Early and accurate diagnosis of Alzheimer's disease (AD) in clinical practice is urgent with advances in AD treatment. Blood biomarker assays are preferential diagnostic tools for widespread clinical use with the advantages of being less invasive, cost effective, and easily accessible, and they have shown good performance in research cohorts. However, in community-based populations with maximum heterogeneity, great challenges are still faced in diagnosing AD based on blood biomarkers in terms of accuracy and robustness. Here, we analyze these challenges, including the confounding impact of systemic and biological factors, small changes in blood biomarkers, and difficulty in detecting early changes. Furthermore, we provide perspectives on several potential strategies to overcome these challenges for blood biomarkers to bridge the gap from research to clinical practice.

Dual active sites over Cu-ZnO-ZrO2 catalysts for carbon dioxide hydrogenation to methanol.

CO2 hydrogenation to methanol is a significant approach to tackle the problem of global warming and simultaneously meet the demand for the portable fuel. Cu-ZnO catalysts with various kinds of promoters have received wide attention. However, the role of promoter and the form of active sites in CO2 hydrogenation are still in debate. Here, various molar ratios of ZrO2 were added into the Cu-ZnO catalysts to tune the distributions of Cu0 and Cu+ species. A volcano-like trend between the ratio of Cu+/ (Cu+ + Cu0) and the amount of ZrO2 is presented, among which the CuZn10Zr (the molar ratio of ZrO2 is 10%) catalyst reaches the highest value. Correspondingly, the maximum value of space-time yield to methanol with 0.65 gMeOH/(gcat·hr) is obtained on CuZn10Zr at reaction conditions of 220°C and 3 MPa. Detailed characterizations demonstrate that dual active sites are proposed during CO2 hydrogenation over CuZn10Zr catalyst. The exposed Cu0 takes participate in the activation of H2, while on the Cu+ species, the intermediate of formate from the co-adsorption of CO2 and H2 prefers to be further hydrogenated to CH3OH than decomposing into the by-product of CO, yielding a high selectivity of methanol.

Inhibiting α1-adrenergic receptor signaling pathway ameliorates AD-type pathologies and behavioral deficits in APPswe/PS1 mouse model.

The role of α1 adrenergic receptors (α1-ARs) signaling pathway in the pathogenesis of Alzheimer's disease (AD) has rarely been investigated. Clarifying the pathophysiological functions of α1-ARs in the AD brain is helpful for better understanding the pathogenesis and screening novel therapeutic targets of AD. This study included 2 arms of in vivo investigations: 1) 6-month-old female APPswe/PS1 mice were intravenously treated with AAV-PHP.eB-shRNA (α1-ARs)-GFP or AAV-PHP.eB-GFP for 3 months. 2) 3-month-old female APPswe/PS1 mice were daily treated with 0.5 mg/kg terazosin or an equal volume of saline for 6 months. SH-SY5Y cell lines bearing human amyloid precursor protein were treated with terazosin or saline for investigating possible mechanisms. α1-ARs knockdown mice exhibited improved behavioral performances in comparison with control mice. α1-ARs knockdown mice had significantly lower brain amyloid burden, as reflected by soluble Aß species, compact and total Aß plaques, than control mice. α1-ARs inhibitor terazosin substantially reduced Aß deposition, attenuated downstream pathologies including tau hyperphosphorylation, glial activation, neuronal loss, synaptic dysfunction et al., and rescued behavioral deficits in APPswe/PS1 mice. In vitro investigation demonstrated that α1-ARs inhibition down-regulated BACE1 expression, and promoted ser9 phosphorylation of GSK-3ß, thus reducing Aß production. This study indicates that inhibition of α1-ARs signaling pathway might represent a promising therapeutic strategy for AD.

Identification of novel drug targets for Alzheimer's disease by integrating genetics and proteomes from brain and blood.

Genome-wide association studies (GWASs) have discovered numerous risk genes for Alzheimer's disease (AD), but how these genes confer AD risk is challenging to decipher. To efficiently transform genetic associations into drug targets for AD, we employed an integrative analytical pipeline using proteomes in the brain and blood by systematically applying proteome-wide association study (PWAS), Mendelian randomization (MR) and Bayesian colocalization. Collectively, we identified the brain protein abundance of 7 genes (ACE, ICA1L, TOM1L2, SNX32, EPHX2, CTSH, and RTFDC1) are causal in AD (P < 0.05/proteins identified for PWAS and MR; PPH4 >80% for Bayesian colocalization). The proteins encoded by these genes were mainly expressed on the surface of glutamatergic neurons and astrocytes. Of them, ACE with its protein abundance was also identified in significant association with AD on the blood-based studies and showed significance at the transcriptomic level. SNX32 was also found to be associated with AD at the blood transcriptomic level. Collectively, our current study results on genetic, proteomic, and transcriptomic approaches has identified compelling genes, which may provide important leads to design future functional studies and potential drug targets for AD.

Blood cell-produced amyloid-ß induces cerebral Alzheimer-type pathologies and behavioral deficits.

It is traditionally believed that cerebral amyloid-beta (Aß) deposits are derived from the brain itself in Alzheimer's disease (AD). Peripheral cells such as blood cells also produce Aß. The role of peripherally produced Aß in the pathogenesis of AD remains unknown. In this study, we established a bone marrow transplantation model to investigate the contribution of blood cell-produced Aß to AD pathogenesis. We found that bone marrow cells (BMCs) transplanted from APPswe/PS1dE9 transgenic mice into wild-type (Wt) mice at 3 months of age continuously expressed human Aß in the blood, and caused AD phenotypes including Aß plaques, cerebral amyloid angiopathy (CAA), tau hyperphosphorylation, neuronal degeneration, neuroinflammation, and behavioral deficits in the Wt recipient mice at 12 months after transplantation. Bone marrow reconstitution in APPswe/PS1dE9 mice with Wt-BMCs at 3 months of age reduced blood Aß levels, and alleviated brain Aß burden, neuronal degeneration, neuroinflammation, and behavioral deficits in the AD model mice at 12 months after transplantation. Our study demonstrated that blood cell-produced Aß plays a significant role in AD pathogenesis, and the elimination of peripheral production of Aß can decrease brain Aß deposition and represents a novel therapeutic approach for AD.

Physiological clearance of amyloid-beta by the kidney and its therapeutic potential for Alzheimer's disease.

Amyloid-ß (Aß) accumulation in the brain is a pivotal event in the pathogenesis of Alzheimer's disease (AD), and its clearance from the brain is impaired in sporadic AD. Previous studies suggest that approximately half of the Aß produced in the brain is cleared by transport into the periphery. However, the mechanism and pathophysiological significance of peripheral Aß clearance remain largely unknown. The kidney is thought to be responsible for Aß clearance, but direct evidence is lacking. In this study, we investigated the impact of unilateral nephrectomy on the dynamic changes in Aß in the blood and brain in both humans and animals and on behavioural deficits and AD pathologies in animals. Furthermore, the therapeutic effects of the diuretic furosemide on Aß clearance via the kidney were assessed. We detected Aß in the kidneys and urine of both humans and animals and found that the Aß level in the blood of the renal artery was higher than that in the blood of the renal vein. Unilateral nephrectomy increased brain Aß deposition; aggravated AD pathologies, including Tau hyperphosphorylation, glial activation, neuroinflammation, and neuronal loss; and aggravated cognitive deficits in APP/PS1 mice. In addition, chronic furosemide treatment reduced blood and brain Aß levels and attenuated AD pathologies and cognitive deficits in APP/PS1 mice. Our findings demonstrate that the kidney physiologically clears Aß from the blood, suggesting that facilitation of Aß clearance via the kidney represents a novel potential therapeutic approach for AD.