scholarly journals Integrated lipidomics and proteomics network analysis highlights lipid and immunity pathways associated with Alzheimer’s disease

2020 ◽  
Author(s):  
Jin Xu ◽  
Giulia Bankov ◽  
Min Kim ◽  
Asger Wretlind ◽  
Jodie Lord ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Brain Atrophy ◽  
Molecular Mechanisms ◽  
Enrichment Analysis ◽  
Integrative Approach ◽  
List Type ◽  
Network Analyses ◽  
Lipid Species ◽  
Protein Modules

AbstractINTRODUCTIONThere is an urgent need to understand the molecular mechanisms underlying Alzheimer’s Disease (AD) to enable early diagnosis and develop effective treatments. Here we aim to investigate Alzheimer’s dementia using an unsupervised lipid, protein and gene multi-omic integrative approach.METHODSA lipidomics dataset (185 AD, 40 MCI and 185 controls) and a proteomics dataset (201 AD patients, 104 MCI individuals and 97 controls) were utilised for weighted gene co-expression network analyses (WGCNA). An additional proteomics dataset (94 AD, 55 MCI and 100 controls) was included for external proteomics validation. Modules created within each modality were correlated with clinical AD diagnosis, brain atrophy measures and disease progression, as well as with each other. Gene Ontology (GO) enrichment analysis was employed to examine the biological processes and molecular and cellular functions for protein modules associated with AD phenotypes. Lipid species were annotated in the lipid modules associated with AD phenotypes. Associations between established AD risk loci and lipid/protein modules that showed high correlation with AD phenotypes were also explored.RESULTSFive of the 20 identified lipid modules and five of the 17 identified protein modules were correlated with AD phenotypes. Lipid modules comprising of phospholipids, triglycerides, sphingolipids and cholesterol esters, correlated with AD risk loci involved in immune response and lipid metabolism. Five protein modules involved in positive regulation of cytokine production, neutrophil mediated immunity, humoral immune responses were correlated with AD risk loci involved in immune and complement systems.DISCUSSIONWe have shown the first multi-omic study linking genes, proteins and lipids to study pathway dysregulation in AD. Results identified modules of tightly regulated lipids and proteins that were strongly associated with AD phenotypes and could be pathology drivers in lipid homeostasis and innate immunity.Research in ContextLipid and protein modules were preserved amongst Alzheimer’s disease (AD) patients, participants with mild cognitive impairment (MCI) and controls. Protein modules were also externally validated.Five lipid and five protein modules out of a total of thirty-seven correlated with clinical AD diagnosis, brain atrophy measurements and the rate of cognitive decline in AD.Lipid and protein modules associated with AD phenotypes showed associations with established AD risk loci involved in lipid and immune pathways.

scholarly journals Integrated lipidomics and proteomics network analysis highlights lipid and immunity pathways associated with Alzheimer’s disease

2020 ◽  
Vol 9 (1) ◽  
Author(s):  
Jin Xu ◽  
◽  
Giulia Bankov ◽  
Min Kim ◽  
Asger Wretlind ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Lipid Metabolism ◽  
Disease Progression ◽  
Brain Atrophy ◽  
Enrichment Analysis ◽  
Integrative Approach ◽  
Network Analyses ◽  
Lipid Species ◽  
Protein Modules

Abstract Background There is an urgent need to understand the pathways and processes underlying Alzheimer’s disease (AD) for early diagnosis and development of effective treatments. This study was aimed to investigate Alzheimer’s dementia using an unsupervised lipid, protein and gene multi-omics integrative approach. Methods A lipidomics dataset comprising 185 AD patients, 40 mild cognitive impairment (MCI) individuals and 185 controls, and two proteomics datasets (295 AD, 159 MCI and 197 controls) were used for weighted gene co-expression network analyses (WGCNA). Correlations of modules created within each modality with clinical AD diagnosis, brain atrophy measures and disease progression, as well as their correlations with each other, were analyzed. Gene ontology enrichment analysis was employed to examine the biological processes and molecular and cellular functions of protein modules associated with AD phenotypes. Lipid species were annotated in the lipid modules associated with AD phenotypes. The associations between established AD risk loci and the lipid/protein modules that showed high correlation with AD phenotypes were also explored. Results Five of the 20 identified lipid modules and five of the 17 identified protein modules were correlated with clinical AD diagnosis, brain atrophy measures and disease progression. The lipid modules comprising phospholipids, triglycerides, sphingolipids and cholesterol esters were correlated with AD risk loci involved in immune response and lipid metabolism. The five protein modules involved in positive regulation of cytokine production, neutrophil-mediated immunity, and humoral immune responses were correlated with AD risk loci involved in immune and complement systems and in lipid metabolism (the APOE ε4 genotype). Conclusions Modules of tightly regulated lipids and proteins, drivers in lipid homeostasis and innate immunity, are strongly associated with AD phenotypes.

Screening novel drug candidates for Alzheimer’s disease by an integrated network and transcriptome analysis

2020 ◽  
Vol 36 (17) ◽  
pp. 4626-4632
Author(s):  
Yonglin Peng ◽  
Meng Yuan ◽  
Juncai Xin ◽  
Xinhua Liu ◽  
Ju Wang
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Molecular Mechanisms ◽  
Enrichment Analysis ◽  
Gene Set Enrichment Analysis ◽  
Functional Enrichment ◽  
Supplementary Information ◽  
Integrated Network ◽  
Drug Candidates ◽  
Novel Drug

Abstract Motivation Alzheimer’s disease (AD) is a serious degenerative brain disease and the most common cause of dementia. The current available drugs for AD provide symptomatic benefit, but there is no effective drug to cure the disease. The emergence of large-scale genomic, pharmacological data provides new opportunities for drug discovery and drug repositioning as a promising strategy in searching novel drug for AD. Results In this study, we took advantage of our increasing understanding based on systems biology approaches on the pathway and network levels and perturbation datasets from the Library of Integrated Network-Based Cellular Signatures to introduce a systematic computational process to discover new drugs implicated in AD. First, we collected 561 genes that have reported to be risk genes of AD, and applied functional enrichment analysis on these genes. Then, by quantifying proximity between 5595 molecule drugs and AD based on human interactome, we filtered out 1092 drugs that were proximal to the disease. We further performed an Inverted Gene Set Enrichment analysis on these drug candidates, which allowed us to estimate effect of perturbations on gene expression and identify 24 potential drug candidates for AD treatment. Results from this study also provided insights for understanding the molecular mechanisms underlying AD. As a useful systematic method, our approach can also be used to identify efficacious therapies for other complex diseases. Availability and implementation The source code is available at https://github.com/zer0o0/drug-repo.git. Supplementary information Supplementary data are available at Bioinformatics online.

scholarly journals Revealing Notch-dependencies in synaptic targets associated with Alzheimer’s disease

2021 ◽  
Author(s):  
A. Perna ◽  
S. Marathe ◽  
R. Dreos ◽  
L. Falquet ◽  
H. Akarsu ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Decline ◽  
Notch Signaling ◽  
Mouse Models ◽  
Molecular Mechanisms ◽  
Pyramidal Neurons ◽  
Synaptic Proteins ◽  
Network Activity ◽  
List Type

AbstractAlzheimer’s disease (AD) is a progressive neurodegenerative disorder and the major cause of dementia. There is evidence that synaptic dysfunction and perturbation of Excitatory/Inhibitory (E/I) balance arise at the early stages of AD, altering the normal neural network activity, and leading to cognitive decline. Recent studies have identified Notch signaling as a contributor of neurodegenerative advancement including AD pathophysiology. As part of the efforts to understand molecular mechanisms and players involved in cognitive decline, we employed transgenic mouse models with Notch1 and RBPJK loss of function (LOF) in pyramidal neurons of the CA fields. Using bulk RNAseq. We have investigated the differential expression of Notch-dependent genes either upon environmental enrichment (EE) or upon Kainate injury (KA). We found a substantial genetic diversity in absence of both Notch1 receptor or Rbpjk transcriptional activator. Among differentially expressed genes, we observed a significant upregulation of Gabra2a in both knockout models, suggesting a role for Notch signaling in the modulation of E/I balance. Upon neuroexcitotoxic stimulation, loss of Rbpjk results in decreased expression of synaptic proteins with neuroprotective effects. We confirmed Nptx2, Npy, Pdch8, TncC as direct Notch1/Rbpjk targets and Bdnf and Scg2 as indirect targets. Finally, we translate these findings into human entorhinal cortex containing the hippocampal region from Alzheimer’s Disease patients performing targeted transcripts analysis. We observe an increased trend for Rbpjk and the ligand DNER but not Notch1 expression. On the other hand, neuron-specific targets, Nptx2, Npy, BDNF and Gabra2a are upregulated during the mild-moderate stage, and decline in the severe phase of the disease. These findings identify Notch as a promising signaling cascade to fine-tune in order to ameliorate synaptic transmission and memory deficits that occur during early phase of the Alzheimer’s Disease.HighlightsLoss of canonical and/or non-canonical Notch1 signaling in pyramidal neurons of the hippocampal CA field mainly affects the post-synaptic compartment.In both RBPJKcKO and Notch1cKO mouse models there is upregulation of GABAergic receptor subunit alpha2 (Gabra2a).The plasticity genes: Npy, Nptx2,Pcdh8 and TncC with neuroprotective functions and known association with Alzheimer’s Disease are direct Notch/Rbpjk targets.During the mild-moderate stage of AD dementia, Notch canonical signaling promotes the expression of neuroprotective proteins, in the attempt of mitigating the effect of the excitatory-inhibitory imbalance. This activity is not observed during severe stages of the disease.

scholarly journals Common genetic signatures of Alzheimer’s disease in Down Syndrome

F1000Research ◽  
2020 ◽  
Vol 9 ◽  
pp. 1299
Author(s):  
Ayati Sharma ◽  
Alisha Chunduri ◽  
Asha Gopu ◽  
Christine Shatrowsky ◽  
Wim E. Crusio ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Down Syndrome ◽  
Early Onset ◽  
Cell Function ◽  
Enrichment Analysis ◽  
Functional Enrichment Analysis ◽  
Functional Enrichment ◽  
Extra Copy ◽  
Network Analyses

Background: People with Down Syndrome (DS) are born with an extra copy of Chromosome (Chr) 21 and many of these individuals develop Alzheimer’s Disease (AD) when they age. This is due at least in part to the extra copy of the APP gene located on Chr 21. By 40 years, most people with DS have amyloid plaques which disrupt brain cell function and increase their risk for AD. About half of the people with DS develop AD and the associated dementia around 50 to 60 years of age, which is about the age at which the hereditary form of AD, early onset AD, manifests. In the absence of Chr 21 trisomy, duplication of APP alone is a cause of early onset Alzheimer’s disease, making it likely that having three copies of APP is important in the development of AD and in DS. In individuals with both DS and AD, early behavior and cognition-related symptoms may include a reduction in social behavior, decreased enthusiasm, diminished ability to pay attention, sadness, fearfulness or anxiety, irritability, uncooperativeness or aggression, seizures that begin in adulthood, and changes in coordination and walking. Methods: We investigate the relationship between AD and DS through integrative analysis of genesets derived from a MeSH query of AD and DS associated beta amyloid peptides, Chr 21, GWAS identified AD risk factor genes, and differentially expressed genes in DS individuals. Results: Unique and shared aspects of each geneset were evaluated based on functional enrichment analysis, transcription factor profile and network analyses. Genes that may be important to both disorders: ACSM1, APBA2, APLP1, BACE2, BCL2L, COL18A1, DYRK1A, IK, KLK6, METTL2B, MTOR, NFE2L2, NFKB1, PRSS1, QTRT1, RCAN1, RUNX1, SAP18 SOD1, SYNJ1, S100B. Conclusions: Our findings indicate that oxidative stress, apoptosis, and inflammation/immune system processes likely underlie the pathogenesis of AD and DS.

scholarly journals A Non-Synonymous SHARPIN Variant is Associated with Limbic Degeneration and Family History of Alzheimer’s Disease

2017 ◽  
Author(s):  
Sourena Soheili-Nezhad ◽  
Neda Jahanshad ◽  
Sebastian Guelfi ◽  
Reza Khosrowabadi ◽  
Andrew J. Saykin ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Independent Component Analysis ◽  
Entorhinal Cortex ◽  
Limbic System ◽  
Brain Atrophy ◽  
Molecular Mechanisms ◽  
Independent Component ◽  
Data Driven ◽  
History Of

AbstractPharmacological progress, basic science and medical practice can benefit from objective biomarkers that assist in early diagnosis and prognostic stratification of diseases. In the field of Alzheimer’s disease (AD), the clinical presentation of early stage dementia may not fulfill any diagnostic criteria for years, and quantifying structural brain changes by magnetic resonance imaging (MRI) has shown promise in the discovery of sensitive biomarkers. Although hippocampal atrophy is often used as an in vivo measure of AD, data-driven neuroimaging has revealed complex patterns of regional brain vulnerability that may not perfectly map to anatomical boundaries. In addition to aiding diagnosis, decoding genetic influences on neuroimaging measures of the disease can enlighten molecular mechanisms of the underlying pathology in living patients and guide the therapeutic design.Here, we aimed to extract a data-driven MRI feature of brain atrophy in AD by decomposing structural neuroimages using independent component analysis (ICA), a method for performing unbiased computational search in high dimensional data spaces. Our study of the AD Neuroimaging Initiative dataset (n=1,100 subjects) revealed a disease-vulnerable feature with a network-like topology, comprising amygdala, hippocampus, fornix and the inter-connecting white-matter tracts of the limbic system. Whole-genome sequencing identified a nonsynonymous variant (rs34173062) in SHARPIN, a gene coding for a synaptic protein, as a significant modifier of this new MRI feature (p=2.1×10−10). The risk variant was brought to replication in the UK Biobank dataset (n=8,428 subjects), where it was associated with reduced cortical thickness in areas co-localizing with those of the discovery sample (left entorhinal cortex p=0.002, right entorhinal cortex p=8.6×10−4; same direction), as well as with the history of AD in both parents (p=2.3×10−6; same direction).In conclusion, our study shows that ICA can transform voxel-wise volumetric measures of the brain into a data-driven feature of neurodegeneration in AD. Structure of the limbic system, as the most vulnerable focus of brain atrophy in AD, is affected by genetic variability of SHARPIN. The elevated risk of dementia in carriers of the minor allele supports engagement of SHARPIN in the disease pathways, and its role in neurotransmitter receptor scaffolding and integrin signaling may inform on new molecular mechanisms of AD pathophysiology.AbbreviationsAlzheimer’s disease (AD), genome-wide association study (GWAS), independent component analysis (ICA), mild cognitive impairment (MCI), medial temporal circuit (MTC), single-nucleotide polymorphism (SNP), tensor-based morphometry (TBM)

Neuroprotective Effects of Ellagic Acid in Alzheimer's Disease: Focus on Underlying Molecular Mechanisms of Therapeutic Potential

2020 ◽  
Vol 26 ◽  
Author(s):  
Nimra Javaid ◽  
Muhammad Ajmal Shah ◽  
Azhar Rasul ◽  
Zunera Chauhdary ◽  
Uzma Saleem ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Ellagic Acid ◽  
Molecular Mechanisms ◽  
Neurodegenerative Disorder ◽  
Therapeutic Potential ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Acetylcholinesterase Activity ◽  
Neuroprotective Effects

: Neurodegeneration is a multifactorial process involved the different cytotoxic pathways that lead towards neuronal cell death. Alzheimer’s disease (AD) is a persistent neurodegenerative disorder that normally has a steady onset yet later on it worsens. The documented evidence of AD neuropathology manifested the neuro-inflammation, increased reactive oxygen, nitrogen species and decreased antioxidant protective process; mitochondrial dysfunction as well as increased level of acetylcholinesterase activity. Moreover, enhanced action of proteins leads towards neural apoptosis which have a vital role in the degeneration of neurons. The inability of commercial therapeutic options to treat AD with targeting single mechanism leads the attraction towards organic drugs. Ellagic acid is a dimer of gallic acid, latest studies expressed that ellagic acid can initiate the numerous cell signaling transmission and decrease the progression of disorders, involved in the degeneration of neurons. The influential property of ellagic acid to protect the neurons in neurodegenerative disorders is due to its antioxidant effect, iron chelating and mitochondrial protective effect. The main goal of this review is to critically analyze the molecular mode of action of ellagic acid against neurodegeneration.

Identifying Alzheimer’s Disease-related miRNA Based on Semi-clustering

2019 ◽  
Vol 19 (4) ◽  
pp. 216-223 ◽  
Author(s):  
Tianyi Zhao ◽  
Donghua Wang ◽  
Yang Hu ◽  
Ningyi Zhang ◽  
Tianyi Zang ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Drug Targets ◽  
Molecular Mechanisms ◽  
Feature Vector ◽  
Mirna Gene ◽  
Interaction Network ◽  
Gene Interaction ◽  
Proteinprotein Interaction ◽  
Synaptic Structures

Background: More and more scholars are trying to use it as a specific biomarker for Alzheimer’s Disease (AD) and mild cognitive impairment (MCI). Multiple studies have indicated that miRNAs are associated with poor axonal growth and loss of synaptic structures, both of which are early events in AD. The overall loss of miRNA may be associated with aging, increasing the incidence of AD, and may also be involved in the disease through some specific molecular mechanisms. Objective: Identifying Alzheimer’s disease-related miRNA can help us find new drug targets, early diagnosis. Materials and Methods: We used genes as a bridge to connect AD and miRNAs. Firstly, proteinprotein interaction network is used to find more AD-related genes by known AD-related genes. Then, each miRNA’s correlation with these genes is obtained by miRNA-gene interaction. Finally, each miRNA could get a feature vector representing its correlation with AD. Unlike other studies, we do not generate negative samples randomly with using classification method to identify AD-related miRNAs. Here we use a semi-clustering method ‘one-class SVM’. AD-related miRNAs are considered as outliers and our aim is to identify the miRNAs that are similar to known AD-related miRNAs (outliers). Results and Conclusion: We identified 257 novel AD-related miRNAs and compare our method with SVM which is applied by generating negative samples. The AUC of our method is much higher than SVM and we did case studies to prove that our results are reliable.

Targeting PPARalpha in Alzheimer's Disease

2018 ◽  
Vol 15 (4) ◽  
pp. 345-354 ◽  
Author(s):  
Barbara D'Orio ◽  
Anna Fracassi ◽  
Maria Paola Cerù ◽  
Sandra Moreno
Keyword(s):  
Oxidative Stress ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Molecular Mechanisms ◽  
Redox Homeostasis ◽  
Antioxidant Response ◽  
Peroxisome Proliferator ◽  
Prevailing Paradigm

Background: The molecular mechanisms underlying Alzheimer's disease (AD) are yet to be fully elucidated. The so-called “amyloid cascade hypothesis” has long been the prevailing paradigm for causation of disease, and is today being revisited in relation to other pathogenic pathways, such as oxidative stress, neuroinflammation and energy dysmetabolism. The peroxisome proliferator-activated receptors (PPARs) are expressed in the central nervous system (CNS) and regulate many physiological processes, such as energy metabolism, neurotransmission, redox homeostasis, autophagy and cell cycle. Among the three isotypes (α, β/δ, γ), PPARγ role is the most extensively studied, while information on α and β/δ are still scanty. However, recent in vitro and in vivo evidence point to PPARα as a promising therapeutic target in AD. Conclusion: This review provides an update on this topic, focussing on the effects of natural or synthetic agonists in modulating pathogenetic mechanisms at AD onset and during its progression. Ligandactivated PPARα inihibits amyloidogenic pathway, Tau hyperphosphorylation and neuroinflammation. Concomitantly, the receptor elicits an enzymatic antioxidant response to oxidative stress, ameliorates glucose and lipid dysmetabolism, and stimulates autophagy.

Genetic Modifiers of Tauopathy in Drosophila

Genetics ◽  
2003 ◽  
Vol 165 (3) ◽  
pp. 1233-1242
Author(s):  
Joshua M Shulman ◽  
Mel B Feany
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Molecular Mechanisms ◽  
Genetic Modifier ◽  
Genetic Modifiers ◽  
Protein Tau ◽  
Major Class ◽  
Drosophila Model ◽  
Tau Kinases

Abstract In Alzheimer's disease and related disorders, the microtubule-associated protein Tau is abnormally hyperphosphorylated and aggregated into neurofibrillary tangles. Mutations in the tau gene cause familial frontotemporal dementia. To investigate the molecular mechanisms responsible for Tau-induced neurodegeneration, we conducted a genetic modifier screen in a Drosophila model of tauopathy. Kinases and phosphatases comprised the major class of modifiers recovered, and several candidate Tau kinases were similarly shown to enhance Tau toxicity in vivo. Despite some clinical and pathological similarities among neurodegenerative disorders, a direct comparison of modifiers between different Drosophila disease models revealed that the genetic pathways controlling Tau and polyglutamine toxicity are largely distinct. Our results demonstrate that kinases and phosphatases control Tau-induced neurodegeneration and have important implications for the development of therapies in Alzheimer's disease and related disorders.

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