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.

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 Combining two large clinical cohorts (AIBL and ADNI) to identify multiple lipid metabolic pathways in prevalent and incident Alzheimer’s disease

2020 ◽  
Author(s):  
Kevin Huynh ◽  
Wei Ling Florence Lim ◽  
Corey Giles ◽  
Kaushala S Jayawardana ◽  
Agus Salim ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Lipid Metabolism ◽  
Disease Onset ◽  
Biological Significance ◽  
Disease Classification ◽  
Imaging Biomarkers ◽  
Holistic View ◽  
Lipid Species ◽  
Mechanistic Investigation

ABSTRACTChanges to lipid metabolism are tightly associated with the onset and pathology of Alzheimer’s disease (AD). Lipids are complex molecules comprising of many isomeric and isobaric species, necessitating detailed analysis to enable interpretation of biological significance. Our expanded targeted lipidomics platform (569 lipid species across 32 lipid (sub)classes) allows for detailed isomeric and isobaric lipid separation. We applied the methodology to examine plasma samples from the Australian Imaging, Biomarkers and Lifestyle flagship study of aging (AIBL, n = 1112) and serum from the Alzheimer’s Disease Neuroimaging Initiative (ADNI, n = 800) studies. Cross sectional analysis using both cohorts identified concordant unique peripheral signatures associated with AD. Specific pathways include; sphingolipids, including GM3 gangliosides, where their acyl composition drove the major associations, and lipids previously associated with dysfunctional lipid metabolism in cardiometabolic disease including the phosphatidylethanolamine and triglyceride classes. Infomation derived from improved isomeric seperation highlighted pathway-specific changes with ether lipids including plasmalogens implicating perixosmal dysfunction in disease pathology. Longitudinal analysis revealed similar lipid signitures in both AIBL and ADNI cohorts with future disease onset. We utilised the two independent studies to train and validate multivariate lipid models that significantly improved disease classification and prediction. Together our results provide a holistic view of the lipidome and its relationship with AD using a comprehensive lipidomics approach, providing targets for further mechanistic investigation.

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 Disease progression modelling from preclinical Alzheimer’s disease (AD) to AD dementia

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Soo Hyun Cho ◽  
Sookyoung Woo ◽  
Changsoo Kim ◽  
Hee Jin Kim ◽  
Hyemin Jang ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Disease Progression ◽  
Disease Assessment ◽  
Time Interval ◽  
Disease Course ◽  
Preclinical Alzheimer’S Disease ◽  
Apoe Ε4 ◽  
Preclinical Ad ◽  
Cognitive Subscale

AbstractTo characterize the course of Alzheimer’s disease (AD) over a longer time interval, we aimed to construct a disease course model for the entire span of the disease using two separate cohorts ranging from preclinical AD to AD dementia. We modelled the progression course of 436 patients with AD continuum and investigated the effects of apolipoprotein E ε4 (APOE ε4) and sex on disease progression. To develop a model of progression from preclinical AD to AD dementia, we estimated Alzheimer’s Disease Assessment Scale-Cognitive Subscale 13 (ADAS-cog 13) scores. When calculated as the median of ADAS-cog 13 scores for each cohort, the estimated time from preclinical AD to MCI due to AD was 7.8 years and preclinical AD to AD dementia was 15.2 years. ADAS-cog 13 scores deteriorated most rapidly in women APOE ε4 carriers and most slowly in men APOE ε4 non-carriers (p < 0.001). Our results suggest that disease progression modelling from preclinical AD to AD dementia may help clinicians to estimate where patients are in the disease course and provide information on variation in the disease course by sex and APOE ε4 status.

scholarly journals The extracellular chaperone Clusterin enhances Tau aggregate seeding in a cellular model

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Patricia Yuste-Checa ◽  
Victoria A. Trinkaus ◽  
Irene Riera-Tur ◽  
Rahmi Imamoglu ◽  
Theresa F. Schaller ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Disease Progression ◽  
Frontotemporal Dementia ◽  
Brain Regions ◽  
Model System ◽  
Cellular Model ◽  
Tau Pathology ◽  
Extracellular Chaperone ◽  
Tau Aggregate

AbstractSpreading of aggregate pathology across brain regions acts as a driver of disease progression in Tau-related neurodegeneration, including Alzheimer’s disease (AD) and frontotemporal dementia. Aggregate seeds released from affected cells are internalized by naïve cells and induce the prion-like templating of soluble Tau into neurotoxic aggregates. Here we show in a cellular model system and in neurons that Clusterin, an abundant extracellular chaperone, strongly enhances Tau aggregate seeding. Upon interaction with Tau aggregates, Clusterin stabilizes highly potent, soluble seed species. Tau/Clusterin complexes enter recipient cells via endocytosis and compromise the endolysosomal compartment, allowing transfer to the cytosol where they propagate aggregation of endogenous Tau. Thus, upregulation of Clusterin, as observed in AD patients, may enhance Tau seeding and possibly accelerate the spreading of Tau pathology.

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