Important Role In Alzheimer's Disease Research Articles

Causal Effects of Kidney Function and Chronic Kidney Disease on Alzheimer's Disease by Analyzing Large-Scale Genome-Wide Association Study Datasets.

Alzheimer's disease (AD) is the leading cause of dementia. Genetic components play an important role in AD and have been widely evaluated by genome-wide association studies (GWAS) and exome sequencing, and some common and rare genetic variants have been identified. In addition to genetic factors, environment factors have a role in AD. Growing evidence from observational studies linked impaired kidney function to cognitive impairment and AD; however, there are inconsistences in these findings. To determine the causal effects of impaired kidney function and chronic kidney disease (CKD) on AD. Mendelian randomization (MR) methods have been widely used to infer causal associations between exposure and outcome. Here, we conducted an MR study to investigate the causal effects of impaired kidney function and CKD on the risk of AD by analyzing large-scale GWAS datasets from FinnGen and CKD Genetics (CKDGen) Consortium. We found no significant but a suggestive effect of CKD on decreased risk of AD using inverse-variance weighted (IVW) (p = 8.46E-02) and simple mode (p = 7.60E-02) methods. We identified a statistically significant effect of the estimated glomerular filtration rate (eGFR) on increased risk of AD using IVW (p = 1.11E-02), weighted median regression (p = 5.60E-03), and weighted mode (p = 2.45E-02) methods. Together, our findings indicate that high eGFR levels may increase the risk of AD. These findings need to be verified in future studies.

A superior near infrared fluorescent probe for revealing the relationship between peroxynitrite and Alzheimer's disease

The typical neurodegenerative Alzheimer's disease (AD) poses an increasing threat to human health as the population ages. Though increasing attention has been drawn for the etiology of AD over decades, regretfully, the exact pathogenesis of AD is not fully elucidated. The elevated levels of ROS are among the major pathological alterations in AD. Among them, peroxynitrite (ONOO-) exhibits a greater impact compared to other reactive oxygen species and plays an important role in AD, but the role ONOO- plays in AD progression remains unclear. In this work, the near-infrared (NIR) fluorophore (benzopyran derivative) was optimized by molecular skeleton modification, and a fluorophore DCM-Cl-OH with better spectral properties was obtained. On this basis, a NIR fluorescence probe DCM-Cl-P with excellent detection performance was obtained. Based on the high selectivity and fast response of the probe to ONOO-, DCM-Cl-P was used to visual detection of ONOO- in living cells and zebrafish, and further demonstrated the excessive accumulation of ONOO- in AD model mice. More importantly, through analysis of the correlation between ONOO- and amyloid-β protein (Aβ), ONOO- and the aggregation of Aβ were closely related and mutually reinforcing was demonstrated and ONOO- underwent significant changes in the early stage of the change of Aβ aggregation, indicating that ONOO- may serve as an early marker of AD. These findings have greatly promoted the research on the intrinsic relationship between ONOO- and AD, and provides a powerful means for pathological research of AD.

Association of Neurotrophic Factors at Midlife With In Vivo Measures of β-Amyloid and Tau Burden 15 Years Later in Dementia-Free Adults.

Neurotrophic factors (NTFs) play an important role in Alzheimer disease (AD) pathophysiology. Brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF) are important NTFs. However, a direct link of BDNF and VEGF circulating levels with in vivo measures of amyloid-β (Aβ) and tau burden remains to be elucidated. We explored the relationship of BDNF and VEGF serum levels with future brain Aβ and tau pathology in a cohort of cognitively healthy, predominantly middle-aged adults and tested for possible effect modifications by sex and menopausal status. This cross-sectional analysis was conducted using data from the Framingham Heart Study (FHS), a community-based cohort study. The study sample included cognitively healthy participants from the FHS Offspring and Third-generation cohorts. BDNF and VEGF were measured in the third-generation cohort during examination cycles 2 (2005-2008) and 1 (2002-2005), respectively, and in the offspring cohort during examination cycle 7 (1998-2001). Participants underwent 11C-Pittsburgh compound B amyloid and 18F-Flortaucipir tau-PET imaging (2015-2021). Linear regression models were used to assess the relationship of serum BDNF and VEGF levels with regional tau and global Aβ, adjusting for potential confounders. Interactions with sex and menopausal status were additionally tested. The sample included 414 individuals (mean age = 41 ± 9 years; 51% female). Continuous measures of BDNF and VEGF were associated with tau signal in the rhinal region after adjustment for potential confounders (β = -0.15 ± 0.06, p = 0.018 and β = -0.19 ± 0.09, p = 0.043, respectively). High BDNF (≥32,450 pg/mL) and VEGF (≥488 pg/mL) levels were significantly related to lower rhinal tau (β = -0.27 ± 0.11, p = 0.016 and β = -0.40 ± 0.14, p = 0.004, respectively) and inferior temporal tau (β = -0.24 ± 0.11, p = 0.028 and β = -0.26 ± 0.13, p = 0.049, respectively). The BDNF-rhinal tau association was observed only among male individuals. Overall, BDNF and VEGF were not associated with global amyloid; however, high VEGF levels were associated with lower amyloid burden in postmenopausal women (β = -1.96 ± 0.70, p = 0.013, per 1 pg/mL). This study demonstrates a robust association between BDNF and VEGF serum levels with in vivo measures of tau almost 2 decades later. These findings add to mounting evidence from preclinical studies suggesting a role of NTFs as valuable blood biomarkers for AD risk prediction.

Qi-fu-yin attenuated cognitive disorders in 5xFAD mice of Alzheimer's disease animal model by regulating immunity.

Cognitive impairment is the main symptom of Alzheimer's disease (AD). Accumulating evidence implicate that immunity plays an important role in AD. Here, we investigated the effect of Qi-fu-yin (QFY) on cognitive impairment and cytokine secretion of 5xFAD mice. We used 2.5-month-old 5xFAD transgenic mice for behavioral tests to observe the changes in cognitive function after QFY treatment. After the behavioral experiment, the whole brain, cortex and plasma of each mouse were collected for soluble Aβ analysis, immunohistochemical experiment and cytokine analysis. Here we found that the treatment of QFY ameliorated the ability of object recognition, passive avoidance responses and the ability of spatial learning and memory in 5xFAD mice. The deposits of β1 - 42 and Aβ1 - 40 were alleviated and the ration of Aβ1 - 42/Aβ1 - 40 was decrease in the plasma and brain of 5xFAD mice administrated with QFY. The administration of QFY promoted the secretion of anti-inflammatory cytokines, IL-5, IL-10 and G-CSF, and reduced the content of proinflammatory cytokines IFN-γ in plasma of 5xFAD mice. Notably, we found that the treatment of QFY decreased the concentration of CCL11 in the brain and plasma of 5xFAD mice. This suggested that QFY improved cognition and reduced Aβ deposits in 5xFAD mice by regulating abnormal immunity in 5xFAD mice. QFY may be as a potential therapeutic agent for AD.

Impact of APOE on amyloid progression in Alzheimer disease

AbstractBackgroundIt is well recognized that β‐amyloid (Aβ) pathology plays an important role in Alzheimer Disease (AD) pathophysiology. The amount of Aβ in the brain varies substantially within both preclinical and symptomatic AD populations. Part of this inter‐individual variability in amyloid pathology may be explained by the genotype variation of Apolipoprotein E (APOE), with the allele e4 found to be the most significant genetic risk factor for late‐onset AD. However, the impact of APOE genotype on the rate of amyloid accumulation is less clear and requires further investigation. In this study, we focus on longitudinal approaches to investigate how APOE genotype influences the trajectories of the Aβ pathology.MethodFor this project, we used longitudinal data of participants from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) and the Washington University Knight Alzheimer Disease Research Center (Knight ADRC). We included 247 participants with available APOE genotype data, and longitudinal measure of Aβ burden via florbetapir (AV45) PET data, see table 1. Imaging PET data from ADNI and ADRC were harmonized using a centiloid conversion. The rate of Aβ accumulation was estimated as the slope of the random coefficient model using all available time points of longitudinal imaging data for each participant, controlling for age, sex, education and cohort. Generalized linear model was used to test the association between APOE genotype and the rate of change in amyloid.ResultThe rate of change in amyloid burden was not significantly different among all APOE genotype groups (Figure 1A; F = 1.64, p = 0.15). When looking specifically at the effect of allele count for APOE‐e4, we observed the rate of change in amyloid burden increased with e4 allele (Figure 1B; F = 4.18, P = 0.02). Pairwise comparison showed significant differences in rate of amyloid accumulation between e4e4 and e2e3 APOE genotype groups (p = 0.04), and between e4e4 and e3e3 APOE genotype groups (p = 0.04), see table 2. There was no significant difference in rate of amyloid accumulation between other genotype groups.ConclusionAPOE e4 increases AD risk by accelerating the amyloid deposition. Future direction will include a larger sample size to investigate the effect of e2 and e3 on amyloid progression in AD.

Changes in arginine metabolism in advanced Alzheimer's patients: Experimental and theoretical analyses

Limited data obtained in studies conducted in recent years suggest that changes in arginine metabolism may be associated with the pathogenesis of Alzheimer's disease (AD). However, the underlying mechanisms of this pathway's effects on the disease are not clear and there are conflicting data. Therefore, in this study, we aimed to determine the levels of l-arginine and its important metabolites and enzymes involved in the pathway in advanced AD patients to examine the change in l-arginine metabolism as inclusively as possible.Serum and plasma samples were obtained from 51 patients diagnosed with advanced AD and 30 volunteer controls. Arginase, Ornithine Decarboxylase (ODC), Arginine Decarboxylase (ADC), and Agmatinase levels in serum samples were determined by enzyme-linked immunosorbent assay (ELISA) and, l-arginine, Ornithine and nitric oxide (NO) levels were determined by colorimetric method. Agmatine levels were measured by high-performance liquid chromatography in the plasma samples of the study groups. Furthermore, in silico molecular docking studies were performed to get preliminary knowledge about the binding interactions of the agmatine with various targets such as AChE, butyrylcholinesterase (BuChE), BACE-1 and tau protein kinase 1 which play an important role in AD pathogenesis.Agmatine and l-arginine levels were found to be significantly lower in the patient group than in the control group. Milder but not statistically significant reductions were observed in all other parameters we measured involved in l-arginine metabolism. Furthermore, NO levels were found to be significantly lower in men with advanced AD patients than in control men. It has been analyzed that agmatine ligand interacts effectively with the studied proteins which play an important role in AD pathogenesis; these interactions were significant and, based on the docking score, occurred in the following order: butyrylcholinesterase (PDB id: 1P0I) > Human acetylcholinesterase > Human tau-protein kinase I.In conclusion, in advanced AD patients, the activity of the l-arginine pathway decreased in general, especially agmatine formation, and this may be due to the decrease in l-arginine levels. Therefore, arginine de novo synthesis may be decreased in advanced AD patients. Furthermore, according to the MolDock binding score, agmatine ligand has a high binding affinity for proteins involved in AD management and/or pathogenesis. Therefore, agmatine may play a role in the pathogenesis of AD by inhibiting the activity of these proteins. However, additional comprehensive studies are needed to clarify these thoughts.

The impact of selective and non-selective medial septum stimulation on hippocampal neuronal oscillations: A study based on modeling and experiments

Alzheimer's disease (AD) is a neurodegenerative disorder with a rising socioeconomic impact on societies. The hippocampus (HPC), which plays an important role in AD, is affected in the early stages. The medial septum (MS) in the forebrain provides major cholinergic input to the HPC and has been shown to play a significant role in generating oscillations in hippocampal neurons. Cholinergic neurons in the basal forebrain are particularly vulnerable to neurodegeneration in AD. To better understand the role of MS neurons including the cholinergic, glutamatergic, and GABAergic subpopulations in generating the well-known brain rhythms in HPC including delta, theta, slow gamma, and fast gamma oscillations, we designed a detailed computational model of the septohippocampal pathway. We validated the results of our model, using electrophysiological recordings in HPC with and without stimulation of the cholinergic neurons in MS using designer receptors exclusively activated by designer drugs (DREADDs) in healthy male ChAT-cre rats. Then, we eliminated 75% of the MS cholinergic neurons in the model to simulate degeneration in AD. A series of selective and non-selective stimulations of the remaining MS neurons were performed to understand the dynamics of oscillation regulation in the HPC during the degenerated state. In this way, appropriate stimulation strategies able to normalize the aberrant oscillations are proposed. We found that selectively stimulating the remaining healthy cholinergic neurons was sufficient for network recovery and compare this to stimulating other subpopulations and a non-selective stimulation of all MS neurons. Our data provide valuable information for the development of new therapeutic strategies in AD and a tool to test and predict the outcome of potential theranostic manipulations.

Alzheimer's Disease and Aging Association: Identification and Validation of Related Genes.

Aging is considered a key risk factor for Alzheimer's disease (AD). This study aimed to identify and validate potential aging-related genes associated with AD using bioinformatics analysis. Datasets GSE36980 and GSE5281 were selected to screen differentially expressed genes (DEGs), and the immune cell correlation analysis and GSEA analysis of DEGs were performed. The intersection with senescence genes was taken as differentially expressed senescence-related genes (DESRGs), and the GSE44770 dataset was used for further validation. The potential biological functions and signaling pathways were determined by GO and KEGG, and the hub genes were identified by 12 algorithms in Cytohubba. The expression of 10 hub genes in different brain regions was determined and single-cell sequencing analysis was performed, and diagnostic genes were further screened by gene expression and receiver operating characteristic (ROC) curve. Finally, a miRNA-gene network of diagnostic genes was constructed and targeted drug prediction was performed. A total of 2137 DEGs were screened from the GSE36980 and GSE5281 datasets, and 278 SRGs were identified from the CellAge database. The overlapping DEGs and SRGs constituted 29 DESRGs, including 14 senescence suppressor genes and 15 senescence inducible genes. The top 10 hub genes, including MDH1, CKB, PSMD14, SMARCA4, PEBP1, DDB2, ITPKB, ATF7IP, YAP1, and EWSR1 were screened. Furthermore, four diagnostic genes were identified: PMSD14, PEBP1, ITPKB, and ATF7IP. The ROC analysis showed that the respective area under the curves (AUCs) of PMSD14, PEBP1, ITPKB, and ATF7IP were 0.732, 0.701, 0.747, and 0.703 in the GSE36980 dataset and 0.870, 0.817, 0.902, and 0.834 in the GSE5281 dataset. In the GSE44770 dataset, PMSD14 (AUC, 0.838) and ITPKB (AUC, 0.952) had very high diagnostic values in the early stage of AD. Finally, based on these diagnostic genes, we found that the drug Abemaciclib is a targeted drug for the treatment of age-related AD. Flutamide can aggravate aging-related AD. The results of this study suggest that cellular SRGs might play an important role in AD. PMSD14, PEBP1, ITPKB, and ATF7IP have the potential as specific biomarkers for the early diagnosis of AD.

Lipids as Early and Minimally Invasive Biomarkers for Alzheimer's Disease.

Alzheimer's disease (AD) is the most common neurodegenerative disorder worldwide. Specifically, typical late-onset AD is a sporadic form with a complex etiology that affects over 90% of patients. The current gold standard for AD diagnosis is based on the determination of amyloid status by analyzing cerebrospinal fluid samples or brain positron emission tomography. These procedures can be used widely as they have several disadvantages (expensive, invasive). As an alternative, blood metabolites have recently emerged as promising AD biomarkers. Small molecules that cross the compromised AD blood-brain barrier could be determined in plasma to improve clinical AD diagnosis at early stages through minimally invasive techniques. Specifically, lipids could play an important role in AD since the brain has a high lipid content, and they are present ubiquitously inside amyloid plaques. Therefore, a systematic review was performed with the aim of identifying blood lipid metabolites as potential early AD biomarkers. In conclusion, some lipid families (fatty acids, glycerolipids, glycerophospholipids, sphingolipids, lipid peroxidation compounds) have shown impaired levels at early AD stages. Ceramide levels were significantly higher in AD subjects, and polyunsaturated fatty acids levels were significantly lower in AD. Also, high arachidonic acid levels were found in AD patients in contrast to low sphingomyelin levels. Consequently, these lipid biomarkers could be used for minimally invasive and early AD clinical diagnosis.

Luteolin ameliorates depression-like behaviors by suppressing ER stress in a mouse model of Alzheimer's disease

Alzheimer's disease (AD) is the most common cause of dementia in the elderly population. Inflammation plays an important role in AD, as microglia respond to several pathological insults, such as Aβ, and exert protective homeostatic functions (anti-inflammatory) and detrimental inflammatory functions (proinflammatory). During the development of AD, chronic inflammation that accompanies aging causes microglial priming, a state of hyperactivation in response to stimulation, indicating that suppressing microglial priming may be a therapeutic intervention for AD. Endoplasmic reticulum (ER) stress is crucial for inflammation through NF-kB and inflammasome activation. To identify natural flavonoids that regulate ER stress, a DNA microarray was performed using the brains of AD model mice after long-term intake of quercetin, after which the connectivity map (CMap) assay was carried out. We found that luteolin suppresses lipopolysaccharide (LPS)-induced interleukin 1β (IL1β) expression by inhibiting ER stress. Immunohistochemical analyses showed that CD68 levels were reduced in the brain after intraperitoneal injection of luteolin in a mouse model of AD, suppressing IL1β production. As shown by behavioral analyses using the tail suspension test (TST) and forced swimming test (FST), depression-like behaviors were ameliorated in luteolin-treated AD model mice. These findings indicate that luteolin prevents ER stress to suppress microglial activation in the brain, improving individual activity.

Methylation factor MRPL15 identified as a potential biological target in Alzheimer's disease.

Alzheimer’s disease (AD) is the most common form of dementia. However, the molecular basis of the development and progression of AD is still unclear. To elucidate the molecular processes related to AD, we obtained the expression profiles and analyzed the differentially expressed genes (DEGs). The genes potentially involved in the AD process were identified by PPI network and STEM analysis. The molecular mechanisms related to the recognition of AD were determined by GSEA and enrichment analysis. The differences from immune cells in AD were calculated. The methylation factors were identified by methylation difference analysis. Among them, MRPL15 was identified as suitable for diagnosing AD. Its expression trend had been verified in GSE5281. Importantly, MRPL15 was also a methylation factor. In addition, macrophages and neutrophils were up-regulated in AD patients. This was consistent with previous immune inflammation responses identified as being involved in the development of AD. The results of the present study revealed the genetic changes and molecular mechanisms involved in the process of the development and deterioration of AD patients. The potential AD risk genes and potential biological targets were identified. It provided evidence that immune inflammation and immune cells play an important role in AD.

Treadmill Exercise Alleviates Brain Iron Dyshomeostasis Accelerating Neuronal Amyloid-β Production, Neuronal Cell Death, and Cognitive Impairment in Transgenic Mice Model of Alzheimer's Disease.

Brain iron increases with age and abnormal brain iron metabolism is proving increasingly likely to be involved in the pathology of Alzheimer's disease (AD). The iron-regulatory effect of furin, a ubiquitously expressed proconvertase, might play an important role in AD. Therefore, there is an urgent need to study the effect of furin on iron regulation in AD. For that purpose, we aimed to determine the role of physical exercise in AD associated with brain iron dyshomeostasis. Treadmill exercise attenuated the AD-related abnormal brain iron regulation by furin in vivo, as demonstrated via experiments in aged APP-C105 mice. Next, we examined whether treadmill exercise decreases excessive iron, directly affecting amyloid-β (Aβ) production through the regulation of α-secretase-dependent processing of amyloid protein precursor (APP) involved in the modulation of furin activity. We first observed that cognitive decline and Aβ-induced neuronal cell death were induced by disruption of APP processing via excess iron-induced disruption of furin activity in aged APP-C105 mice. The induced cognitive decline and cell death were attenuated by treadmill exercise. This result suggests that treadmill exercise alleviated cognitive decline and Aβ-induced neuronal cell death by promoting α-secretase-dependent processing of APP through low iron-induced enhancement of furin activity. This is concomitant with decreasing levels of lipid peroxidation products and promoting antioxidant defense enzyme capacities. Therefore, iron-targeted therapeutic strategies involving treadmill exercise might be useful for patients with AD.

Associations of Infectious Agents with Alzheimer's Disease: A Systematic Review and Meta-Analysis.

The role of infectious agents in the development of Alzheimer's disease (AD) has long been debated, however, uncertainties still persist. We aimed to illuminate the associations between infectious agents and risk of AD comprehensively. Studies examining the associations between AD and infectious agents were identified through a systematic search of PubMed, Embase, and Cochrane library. A random-effects meta-analysis was conducted. Publication bias was explored using funnel plot. Fifty-one studies were included in the systematic review, of which forty-seven studies with 108,723 participants and 4,039 AD cases were eligible for meta-analysis. Evidence based on case control studies demonstrated that Chlamydia pneumoniae [odds ratio (OR): 4.39, 95% CI = 1.81-10.67; I2 = 68%)], Human herpes virus-6 (OR: 3.97, 95% CI = 2.04-7.75; I2 = 0%, Epstein-Barr virus (OR:1.45, 95% CI = 1.00-2.08; I2 = 0%), Herpes simplex virus-1 (OR:1.34, 95% CI = 1.02-1.75; I2 = 0%), and the Herpesviridae family (OR:1.41, 95% CI = 1.15-1.74; I2 = 12%) infection were associated with a higher risk of AD. No significant evidence of publication bias was found. These findings strengthened the evidence that infection may play an important role in AD. Additional research is required to determine whether treatment strategies targeting infectious diseases to prevent AD are viable in the future.

Eicosapentaenoic Acid-Enriched Phosphatidylcholine Mitigated Aβ1-42-Induced Neurotoxicity via Autophagy-Inflammasome Pathway.

Recent studies indicated that neuroinflammation contributes to the exacerbation of Alzheimer's disease (AD) and plays an important role in AD. The NOD-like receptor protein 3 (NLRP3) inflammasome, which is an important component of innate immune system, is associated with a wide range of human central nervous system disorders, including AD. Most of the studies focus on the protective effects of docosahexaenoic acid (DHA) in AD, but eicosapentaenoic acid (EPA) has rarely been involved. Here, we investigate the effects of EPA in the forms of phosphatidylcholine (EPA-PC) and ethyl esters (EPA-EE) in improving Aβ1-42-induced neurotoxicity. The spatial memory ability and the biochemical changes in the hippocampus were measured, including glial cell activation, tumor necrosis factor α production, NLRP3 inflammasome activation, and autophagic flux. The present results showed that the AD rats were significantly protected from spatial memory loss by the supplementation (EPA + DHA = 60 mg/kg, i.g., 20 days) of EPA-PC, while EPA-EE showed no significant benefit. Further mechanism studies suggested that EPA-PC could inhibit Aβ-induced neurotoxicity by alleviating NLRP3 inflammasome activation and enhancing autophagy. These findings indicate that EPA could improve cognitive deficiency in Aβ1-42-induced AD rats via autophagic inflammasomal pathway and the bioactivity differs in its molecular form.

Reliable determination of new lipid peroxidation compounds as potential early Alzheimer Disease biomarkers

Lipid peroxidation plays an important role in Alzheimer Disease, so corresponding metabolites found in urine samples could be potential biomarkers. The aim of this work is to develop a reliable ultra-performance liquid chromatography-tandem mass spectrometry analytical method to determine a new set of lipid peroxidation compounds in urine samples.Excellent sensitivity was achieved with limits of detection between 0.08 and 17 nmol L−1, which renders this method suitable to monitor analytes concentrations in real samples. The method's precision was satisfactory with coefficients of variation around 5–17% (intra-day) and 8–19% (inter-day). The accuracy of the method was assessed by analysis of spiked urine samples obtaining recoveries between 70% and 120% for most of the analytes. The utility of the described method was tested by analyzing urine samples from patients early diagnosed with mild cognitive impairment or mild dementia Alzheimer Disease following the clinical standard criteria. As preliminary results, some analytes (17(RS)−10-epi-SC-Δ15−11-dihomo-IsoF, PGE2) and total parameters (Neuroprostanes, Isoprostanes, Isofurans) show differences between the control and the clinical groups. So, these analytes could be potential early Alzheimer Disease biomarkers assessing the patients’ pro-oxidant condition.

GLP-1 receptor agonists downregulate aberrant GnT-III expression in Alzheimer's disease models through the Akt/GSK-3β/β-catenin signaling

Alterations of glycoprotein glycans contribute to a wide variety of diseases. Bisecting N-acetylglucosamine (GlcNAc) levels increased in the cerebrospinal fluid of most Alzheimer's disease (AD) patients, and the mRNA levels of N-acetylglucosaminyltransferase III (GnT-III), a glycosyltransferase responsible for synthesizing a bisecting GlcNAc residue, were found highly expressed in the brains of AD patients. In our previous studies, glucagon-like peptide-1 (GLP-1) and its mimetics showed neuroprotective effects. Here, we confirmed that four weeks' treatment of exendin-4 could rescue memory deficits and neuropathological changes in APP/PS1 mice. We further explored the underlying mechanism and especially the role of GnT-III in it. We demonstrated for the first time that the levels of GnT-III and bisecting GlcNAc were increased in APP/PS1 mice and Aβ25-35-treated PC12 cells, and GLP-1 receptor agonists (GLP-1RA) could downregulate aberrant neuronal expression of GnT-III and bisecting GlcNAc. We also found that GLP-1RA recovered the phosphorylation levels of Akt (Ser473) and GSK-3β (Ser9) and the levels of β-catenin in mice and cell models. Furthermore, the results indicated that inhibitor LY294002 attenuated these effects of GLP-1RA in PC12 cells, and β-catenin siRNA abolished the effect of GLP-1RA on GnT-III. In summary, our results suggest that GnT-III plays an important role in AD and GLP-1RA could downregulate aberrant GnT-III expression through the Akt/GSK-3β/β-catenin signaling pathway in neurons.

Three-way interaction model to trace the mechanisms involved in Alzheimer’s disease transgenic mice

Alzheimer's disease (AD) is the most common cause for dementia in human. Currently, more than 46 million people in the world suffer from AD and it is estimated that by 2050 this number increases to more than 131 million. AD is considered as a complex disease. Therefore, understanding the mechanism of AD is a universal challenge. Nowadays, a huge number of disease-related high-throughput “omics” datasets are freely available. Such datasets contain valuable information about disease-related pathways and their corresponding gene interactions. In the present work, a three-way interaction model is used as a novel approach to understand AD-related mechanisms. This model can trace the dynamic nature of co-expression relationship between two genes by introducing their link to a third gene. Apparently, such relationships cannot be traced by the classical two-way interaction model. Liquid association method was applied to capture the statistically significant triplets which are involved in three-way interaction. Subsequently, gene set enrichment analysis (GSEA) and gene regulatory network (GRN) inference were applied to analyze the biological relevance of the statistically significant triplets. The results of this study suggest that the innate immunity processes are important in AD. Specifically, our results suggest that H2-Ob as the switching gene and the gene pair {Csf1r, Milr1} form a statistically significant and biologically relevant triplet, which may play an important role in AD. We propose that the homeostasis-related link between mast cells and microglia is presumably controlled with H2-Ob expression levels as a switching gene.

IMMUNOMODULATORY EFFECT OF CORD BLOOD-DERIVED MULTIPOTENT STEM CELLS ON LYMPHOCYTES OF PATIENTS WITH ALZHEIMER’S DISEASE

Alzheimer's disease (AD) is a progressive neurodegenerative disease. Studies have found that inflammation in brain and peripheral circulation system plays an important role in AD. Human cord blood-derived multipotent stem cells (CB-SCs) is a new kind of stem cells which could modulate autoimmune responses by altering regulatory T cells (Tregs). We intend to investigate the immunomodulatory effect of CB-SCs on peripheral blood lymphocytes (LCs) of patients with AD and to further explore its therapeutic potency for AD. 1) CB-SCs were isolated from human cord blood and cultivated under the condition of 35°C, 8%CO2 for about 10 days. 2) LCs were isolated from peripheral blood of AD patients, and then cocultivated with CB-SCs for 3 days under the condition with or without phytohaemagglutinin-P (PHA-P) which can stimulate the proliferation of LCs. 3) The levels of cytokines including IL-1, IL-4 and IL-10 in the supernatant were detected via enzyme-linked immuno sorbent assay (ELISA). 4) The percentage of Tregs and the positive ratio of their functional cytokines such as IL-10, TGF-β1 were examined via flow cytometry. 1) CB-SCs could inhibit proliferation and aggregation of LCs induced by PHA-P. 2) The level of IL-1 worked as pro-inflammatory factor was dramatically decreased in the LCs co-cultured with CB-SCs group, while the level of the anti-inflammatory factors including IL-4 and IL-10 were significantly increased. 3) The ratio of CD4+/CD8+ T cells was significantly declined in the both co-cultured groups. 4) The proportion of Tregs was increased significantly in the LCs co-cultured with CB-SCs group that were not stimulated by PHA-P. Whereas, under the stimulation of PHA-P, the anti-inflammatory proteins expressed in the Tregs were raised significantly.

Systematic identification of differential gene network to elucidate Alzheimer's disease

We focus on revealing the mechanism of Alzheimer's disease (AD) by network analysis.We present a novel method to construct a gene network by integrating omics data.The gene network, maintaining the specificity of AD, was statistically optimized.Potential genes and modules that can elucidate a mechanism of AD were identified.We demonstrated the epigenetic factor and ribosomal process are associated with AD. Alzheimer's disease (AD) is a genetically complex neurodegenerative diseases and its pathological mechanism has not been fully discovered. The mechanism of AD can be inferred by elucidating how molecular entities are interacting on the pathway level and how some pathways collectively influence the occurrence of the disease. Such an analysis is considerably complex and cannot be manually performed by experts. It can be solved by integrating huge heterogeneous dataset and systematically building an intelligent system which model molecular network and analyze the causality. Here, we present a novel method to construct an optimized AD-specific differential gene network by integrating a high-confidence interactome and gene expression data. In order to consider an epigenetic factor, we identified differentially methylated genes in AD and the results were projected on the network for mechanism analysis. Through diverse topological analysis and functional enrichment tests, we experimentally demonstrated that the several potential genes and sub networks were significantly related with AD and they could be used to elucidate the molecular mechanism. Taken the experimental results and literature studies together, we newly discovered that ribosomal process-related genes and DNA methylation might play an important role in AD. The proposed system is applicable not only to AD but also to various complex genetic disease models that require new molecular mechanism analysis based on network.

Down-regulation of glutamatergic terminals (VGLUT1) driven by Aβ in Alzheimer's disease.

Alzheimer's disease (AD) is characterized phenotypically by memory impairment, histologically by accumulation of pTau and β-amyloid peptide and morphologically by a loss of nerve terminals in cortical and hippocampal regions. As glutamate is the principle excitatory neurotransmitter of the central nervous system (CNS), the glutamatergic system may play an important role in AD. To date, not many studies have addressed the deleterious effects of Aβ on glutamatergic terminals; therefore the aim of this study was to investigate how Aβ affects glutamatergic terminals and to assess the extent to which alterations in the glutamatergic neurotransmission could impact susceptibility to the illness. The present study shows that Aβ caused a loss of glutamatergic terminals, measured by VGLUT1 protein levels, in Tg2576 primary cell cultures, Tg2576 mice and AD patient brains, and also when Aβ was added exogenously to hippocampal cell cultures. Interestingly, no correlation was found between cognition and decreased VGLUT1 levels. Moreover, when Aβ1-42 was intracerebroventricularlly administered into VGLUT1+/- mice, altered synaptic plasticity and increased neuroinflammation was observed in the hippocampus of those animals. In conclusion, the present study not only revealed susceptibility of glutamatergic nerve terminals to Aβ induced toxicity but also underlined the importance of VGLUT1 in the progression of AD, as the decrease of this protein levels could increase the susceptibility to subsequent deleterious inputs by exacerbating Aβ induced neuroinflammation and synaptic plasticity disruption. © 2016 Wiley Periodicals, Inc.