scholarly journals TREM2 Limits Progression of Deficits and Spreading of Tau Pathology in Mice

2021 ◽  
Author(s):  
Astrid F. Feiten ◽  
Carol Au ◽  
Annika van Hummel ◽  
Julia van der Hoven ◽  
Yuanyuan Deng ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Association Studies ◽  
Amyloid Β ◽  
Distinct Pattern ◽  
Genome Wide Association Studies ◽  
Tau Pathology ◽  
Functional Deficits ◽  
Genome Wide ◽  
Deficient Mice

Abstract Background. Amyloid-β (Aβ) and tau form pathogenic lesions in Alzheimer’s disease (AD) brains. As ΑD clinically progresses, tau pathology propagates in a very distinct pattern between connected brain areas. The molecular mechanisms underlying this tau pathology spread remain largely unknown. Genome-wide association studies have identified polymorphisms in triggering receptor expressed on myeloid cells 2 ( TREM2 ) as genetic risk factors for AD and regulators of Aβ pathology-dependent tau propagation. Whether TREM2 contributes to neuron-to-neuron spreading of pathological tau remains unknown.Methods. Here, we crossed Trem2- deficient mice with P301S tau transgenic TAU58 mice and subjected the mice to behavioral testing and assessed neuropathology. Microglial activation states were determined using cytometry by of flight (CyTOF) and quantitative PCR. Tau spreading was assessed in vivo using tracing of focal tau expression.Results. Trem2 depletion significantly aggravated tau-induced early-onset motor and behavioural deficits. Neuropathologically, Trem2 reduction increased the number of hyperphosphorylated tau lesions in young TAU58 brains and reduced disease-associated microglia. Direct assessment of inter-neuronal spread of tau in vivo revealed significantly enhanced propagation of tau in the absence of Trem2 , suggesting that microglial TREM2 limits the progression of tau pathology in disease.Conclusion. Taken together, our data suggests that reduced TREM2 function accelerates the onset and progression of functional deficits and tau neuropathology in tau transgenic mice, which is - at least in part - due to increased tau spreading. Therefore, reduced TREM2 function may contribute to early AD by augmenting tau toxicity and its inter-neuronal propagation.

scholarly journals Humanized TREM2 mice reveal microglia-intrinsic and -extrinsic effects of R47H polymorphism

2018 ◽  
Vol 215 (3) ◽  
pp. 745-760 ◽  
Author(s):  
Wilbur M. Song ◽  
Satoru Joshita ◽  
Yingyue Zhou ◽  
Tyler K. Ulland ◽  
Susan Gilfillan ◽  
...  
Keyword(s):  
Late Onset ◽  
Association Studies ◽  
Amyloid Β ◽  
Genome Wide Association Studies ◽  
Genome Wide ◽  
Soluble Trem2 ◽  
The Common ◽  
Late Onset Dementia

Alzheimer’s disease (AD) is a neurodegenerative disease that causes late-onset dementia. The R47H variant of the microglial receptor TREM2 triples AD risk in genome-wide association studies. In mouse AD models, TREM2-deficient microglia fail to proliferate and cluster around the amyloid-β plaques characteristic of AD. In vitro, the common variant (CV) of TREM2 binds anionic lipids, whereas R47H mutation impairs binding. However, in vivo, the identity of TREM2 ligands and effect of the R47H variant remain unknown. We generated transgenic mice expressing human CV or R47H TREM2 and lacking endogenous TREM2 in the 5XFAD AD model. Only the CV transgene restored amyloid-β–induced microgliosis and microglial activation, indicating that R47H impairs TREM2 function in vivo. Remarkably, soluble TREM2 was found on neurons and plaques in CV- but not R47H-expressing 5XFAD brains, although in vitro CV and R47H were shed similarly via Adam17 proteolytic activity. These results demonstrate that TREM2 interacts with neurons and plaques duing amyloid-β accumulation and R47H impairs this interaction.

scholarly journals Novel Alzheimer risk genes determine the microglia response to amyloid-β but not to TAU pathology

2018 ◽  
Author(s):  
Annerieke Sierksma ◽  
Ashley Lu ◽  
Evgenia Salta ◽  
Renzo Mancuso ◽  
Jesus Zoco ◽  
...  
Keyword(s):  
Mouse Models ◽  
Genetic Risk ◽  
Association Studies ◽  
Amyloid Β ◽  
Polygenic Risk Score ◽  
Genome Wide Association Studies ◽  
Tau Pathology ◽  
Data Set ◽  
Risk Genes ◽  
Genome Wide

AbstractBackgroundThousands of SNPs associated with risk of Alzheimer’s disease (AD) in genome-wide association studies (GWAS) do not reach genome-wide significance. When combined, they contribute however to a highly predictive polygenic risk score. The relevance of these subthreshold risk genes to disease, and how their combined predictive power translates into functionally relevant disease pathways, is unknown. We investigate here at the genome-wide level and in an unbiased way to what extent AD risk genes show altered gene expression in the context of increasing Aβ or Tau pathology in mouse models of AD.MethodsWe used an existing GWAS data set to generate lists of candidate AD genes at different levels of significance. We performed transcriptomic analysis on wild-type and transgenic APP/PS1 (APPtg) and Thy-TAU22 (TAUtg) mouse models at early and late stage of disease. We used unbiased weighted gene co-expression network analysis (WGCNA) to identify clusters of co-regulated genes responsive to Aβ or TAU pathology. Gene set enrichment was used to identify clusters that were enriched for AD risk genes.FindingsConsistent and significant enrichment of AD risk genes was found in only one out of 63 coexpression modules. This module is highly responsive to Aβ but not to TAU pathology. We identify in this module 18 AD risk genes (p-value=6·5e-11) including 11 new ones, GPC2, TREML2, SYK, GRN, SLC2A5, SAMSN1, PYDC1, HEXB, RRBP1, LYN and BLNK. All are expressed in microglia, have a binding site for the transcription factor SPI1 (PU.1), and become significantly upregulated when exposed to Aβ. A subset regulates FC-gamma receptor mediated phagocytosis.InterpretationGenetic risk of AD is functionally translated into a microglia pathway responsive to Aβ pathology. This insight integrates aspects of the amyloid hypothesis with genetic risk associated to sporadic AD.

Vascular contributions to cognitive impairment and dementia: the emerging role of 20-HETE

2021 ◽  
Vol 135 (15) ◽  
pp. 1929-1944
Author(s):  
Ezekiel Gonzalez-Fernandez ◽  
Yedan Liu ◽  
Alexander P. Auchus ◽  
Fan Fan ◽  
Richard J. Roman
Keyword(s):  
Cognitive Impairment ◽  
Association Studies ◽  
Amyloid Β ◽  
Genome Wide Association Studies ◽  
Genome Wide ◽  
Cerebrovascular Risk ◽  
Potent Vasoconstrictor ◽  
Multiple Drugs ◽  
Epidemiology Studies

Abstract The accumulation of extracellular amyloid-β (Aβ) and intracellular hyperphosphorylated τ proteins in the brain are the hallmarks of Alzheimer’s disease (AD). Much of the research into the pathogenesis of AD has focused on the amyloid or τ hypothesis. These hypotheses propose that Aβ or τ aggregation is the inciting event in AD that leads to downstream neurodegeneration, inflammation, brain atrophy and cognitive impairment. Multiple drugs have been developed and are effective in preventing the accumulation and/or clearing of Aβ or τ proteins. However, clinical trials examining these therapeutic agents have failed to show efficacy in preventing or slowing the progression of the disease. Thus, there is a need for fresh perspectives and the evaluation of alternative therapeutic targets in this field. Epidemiology studies have revealed significant overlap between cardiovascular and cerebrovascular risk factors such as hypertension, diabetes, atherosclerosis and stroke to the development of cognitive impairment. This strong correlation has given birth to a renewed focus on vascular contributions to AD and related dementias. However, few genes and mechanisms have been identified. 20-Hydroxyeicosatetraenoic acid (20-HETE) is a potent vasoconstrictor that plays a complex role in hypertension, autoregulation of cerebral blood flow and blood–brain barrier (BBB) integrity. Multiple human genome-wide association studies have linked mutations in the cytochrome P450 (CYP) 4A (CYP4A) genes that produce 20-HETE to hypertension and stroke. Most recently, genetic variants in the enzymes that produce 20-HETE have also been linked to AD in human population studies. This review examines the emerging role of 20-HETE in AD and related dementias.

scholarly journals Genetic basis of intracranial aneurysm formation and rupture: clinical implications in the postgenomic era

2019 ◽  
Vol 47 (1) ◽  
pp. E10 ◽  
Author(s):  
Nardin Samuel ◽  
Ivan Radovanovic
Keyword(s):  
Intracranial Aneurysm ◽  
Genetic Basis ◽  
Molecular Mechanisms ◽  
Aneurysmal Subarachnoid Hemorrhage ◽  
Association Studies ◽  
Genome Wide Association Studies ◽  
Genetic Aberrations ◽  
Aneurysm Formation ◽  
Genome Wide ◽  
Risk Of Rupture

OBJECTIVEDespite the prevalence and impact of intracranial aneurysms (IAs), the molecular basis of their pathogenesis remains largely unknown. Moreover, there is a dearth of clinically validated biomarkers to efficiently screen patients with IAs and prognosticate risk for rupture. The aim of this study was to survey the literature to systematically identify the spectrum of genetic aberrations that have been identified in IA formation and risk of rupture.METHODSA literature search was performed using the Medical Subject Headings (MeSH) system of databases including PubMed, EMBASE, and Google Scholar. Relevant studies that reported on genetic analyses of IAs, rupture risk, and long-term outcomes were included in the qualitative analysis.RESULTSA total of 114 studies were reviewed and 65 were included in the qualitative synthesis. There are several well-established mendelian syndromes that confer risk to IAs, with variable frequency. Linkage analyses, genome-wide association studies, candidate gene studies, and exome sequencing identify several recurrent polymorphic variants at candidate loci, and genes associated with the risk of aneurysm formation and rupture, including ANRIL (CDKN2B-AS1, 9p21), ARGHEF17 (11q13), ELN (7q11), SERPINA3 (14q32), and SOX17 (8q11). In addition, polymorphisms in eNOS/NOS3 (7q36) may serve as predictive markers for outcomes following intracranial aneurysm rupture. Genetic aberrations identified to date converge on posited molecular mechanisms involved in vascular remodeling, with strong implications for an associated immune-mediated inflammatory response.CONCLUSIONSComprehensive studies of IA formation and rupture have identified candidate risk variants and loci; however, further genome-wide analyses are needed to identify high-confidence genetic aberrations. The literature supports a role for several risk loci in aneurysm formation and rupture with putative candidate genes. A thorough understanding of the genetic basis governing risk of IA development and the resultant aneurysmal subarachnoid hemorrhage may aid in screening, clinical management, and risk stratification of these patients, and it may also enable identification of putative mechanisms for future drug development.

scholarly journals Challenges and progress in interpretation of non-coding genetic variants associated with human disease

2017 ◽  
Vol 242 (13) ◽  
pp. 1325-1334 ◽  
Author(s):  
Yizhou Zhu ◽  
Cagdas Tazearslan ◽  
Yousin Suh
Keyword(s):  
Molecular Mechanisms ◽  
Target Genes ◽  
Disease Risk ◽  
Association Studies ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Genetic Associations ◽  
Functional Interpretation ◽  
Genome Wide ◽  
Coding Variants

Genome-wide association studies have shown that the far majority of disease-associated variants reside in the non-coding regions of the genome, suggesting that gene regulatory changes contribute to disease risk. To identify truly causal non-coding variants and their affected target genes remains challenging but is a critical step to translate the genetic associations to molecular mechanisms and ultimately clinical applications. Here we review genomic/epigenomic resources and in silico tools that can be used to identify causal non-coding variants and experimental strategies to validate their functionalities. Impact statement Most signals from genome-wide association studies (GWASs) map to the non-coding genome, and functional interpretation of these associations remained challenging. We reviewed recent progress in methodologies of studying the non-coding genome and argued that no single approach allows one to effectively identify the causal regulatory variants from GWAS results. By illustrating the advantages and limitations of each method, our review potentially provided a guideline for taking a combinatorial approach to accurately predict, prioritize, and eventually experimentally validate the causal variants.

scholarly journals Multivariate genome-wide association studies on the tissue compartments of human brain identify novel loci underpinning brain development and neuropsychiatric outcomes.

2021 ◽  
Author(s):  
Chun Chieh Fan ◽  
Robert Loughnan ◽  
Diliana Pechva ◽  
Chi-Hua Chen ◽  
Donald Hagler ◽  
...  
Keyword(s):  
Human Brain ◽  
Molecular Mechanisms ◽  
Association Studies ◽  
Risk Tolerance ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Imaging Features ◽  
Genome Wide ◽  
Neuropsychiatric Diseases ◽  
Tissue Compartments

It is important to understand the molecular determinants for microstructures of human brain. However, past genome-wide association studies (GWAS) on microstructures of human brain have had limited results due to methodological constraints. Here, we adopt advanced imaging processing methods and multivariate GWAS on two large scale imaging genetic datasets (UK Biobank and Adolescent Brain Cognitive Development study) to identify and validate key genetic association signals. We discovered 503 unique genetic loci that explained more than 50% of the average heritability across imaging features sensitive to tissue compartments. The genome-wide signals are strongly overlapped with neuropsychiatric diseases, cognitive functions, risk tolerance, and immune responses. Our results implicate the shared molecular mechanisms between tissue microstructures of brain and neuropsychiatric outcomes with astrocyte involvement in the early developmental stage.

scholarly journals Statins Stimulate Hepatic Glucose Production via the miR-183/96/182 Cluster

2019 ◽  
Author(s):  
Tyler J. Marquart ◽  
Ryan M. Allen ◽  
Mary R. Chen ◽  
Gerald W. Dorn ◽  
Scot J. Matkovich ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Association Studies ◽  
Hepatic Glucose Production ◽  
Ldl Receptor ◽  
Density Lipoprotein ◽  
Hepatic Clearance ◽  
Glucose Production ◽  
Genome Wide Association Studies ◽  
Medical Advance

Statins are the most common pharmacologic intervention in hypercholesterolemic patients, and their use is recognized as a key medical advance leading to a 50% decrease in deaths from heart attack or stroke over the past 30 years. The atheroprotective outcomes of statins are largely attributable to the accelerated hepatic clearance of low-density lipoprotein (LDL)-cholesterol from circulation, following the induction of the LDL receptor. However, multiple studies suggest that these drugs exert additional LDL–independent effects. The molecular mechanisms behind these so-called pleiotropic effects of statins, either beneficial or undesired, remain largely unknown. Here we determined the coding transcriptome, miRNome, and RISCome of livers from mice dosed with saline or atorvastatin to define a novel in vivo epitranscriptional regulatory pathway that links statins to hepatic gluconeogenesis, via the SREBP2–miR-183/96/182–TCF7L2 axis. Notably, multiple genome-wide association studies identified TCF7L2 (transcription factor 7 like 2) as a candidate gene for type 2 diabetes, independent of ethnicity. Conclusion: our data reveal an unexpected link between cholesterol and glucose metabolism, provides a mechanistic explanation to the elevated risk of diabetes recently observed in patients taking statins, and identifies the miR-183/96/182 cluster as an attractive pharmacological candidate to modulate non-canonical effects of statins.

scholarly journals An integrated platform to systematically identify causal variants and genes for polygenic human traits

2019 ◽  
Author(s):  
Damien J. Downes ◽  
Ron Schwessinger ◽  
Stephanie J. Hill ◽  
Lea Nussbaum ◽  
Caroline Scott ◽  
...  
Keyword(s):  
Genetic Variants ◽  
Association Studies ◽  
Significant Proportion ◽  
Genome Wide Association Studies ◽  
Effector Genes ◽  
Genome Wide ◽  
Common Genetic Variants ◽  
Integrated Platform ◽  
Causal Variants

ABSTRACTGenome-wide association studies (GWAS) have identified over 150,000 links between common genetic variants and human traits or complex diseases. Over 80% of these associations map to polymorphisms in non-coding DNA. Therefore, the challenge is to identify disease-causing variants, the genes they affect, and the cells in which these effects occur. We have developed a platform using ATAC-seq, DNaseI footprints, NG Capture-C and machine learning to address this challenge. Applying this approach to red blood cell traits identifies a significant proportion of known causative variants and their effector genes, which we show can be validated by direct in vivo modelling.

scholarly journals Genomic dissection of 43 serum urate-associated loci provides multiple insights into molecular mechanisms of urate control

2019 ◽  
Author(s):  
James Boocock ◽  
Megan Leask ◽  
Yukinori Okada ◽  
Hirotaka Matsuo ◽  
Yusuke Kawamura ◽  
...  
Keyword(s):  
Gene Expression ◽  
Molecular Mechanisms ◽  
Association Studies ◽  
Organic Anion ◽  
Serum Urate ◽  
Regulatory Function ◽  
Eqtl Analysis ◽  
Genome Wide Association Studies ◽  
Genome Wide ◽  
Causal Genes

AbstractSerum urate is the end-product of purine metabolism. Elevated serum urate is causal of gout and a predictor of renal disease, cardiovascular disease and other metabolic conditions. Genome-wide association studies (GWAS) have reported dozens of loci associated with serum urate control, however there has been little progress in understanding the molecular basis of the associated loci. Here we employed trans-ancestral meta-analysis using data from European and East Asian populations to identify ten new loci for serum urate levels. Genome-wide colocalization with cis-expression quantitative trait loci (eQTL) identified a further five new loci. By cis- and trans-eQTL colocalization analysis we identified 24 and 20 genes respectively where the causal eQTL variant has a high likelihood that it is shared with the serum urate-associated locus. One new locus identified was SLC22A9 that encodes organic anion transporter 7 (OAT7). We demonstrate that OAT7 is a very weak urate-butyrate exchanger. Newly implicated genes identified in the eQTL analysis include those encoding proteins that make up the dystrophin complex, a scaffold for signaling proteins and transporters at the cell membrane; MLXIP that, with the previously identified MLXIPL, is a transcription factor that may regulate serum urate via the pentose-phosphate pathway; and MRPS7 and IDH2 that encode proteins necessary for mitochondrial function. Trans-ancestral functional fine-mapping identified six loci (RREB1, INHBC, HLF, UBE2Q2, SFMBT1, HNF4G) with colocalized eQTL that contained putative causal SNPs (posterior probability of causality > 0.8). This systematic analysis of serum urate GWAS loci has identified candidate causal genes at 19 loci and a network of previously unidentified genes likely involved in control of serum urate levels, further illuminating the molecular mechanisms of urate control.Author SummaryHigh serum urate is a prerequisite for gout and a risk factor for metabolic disease. Previous GWAS have identified numerous loci that are associated with serum urate control, however, only a small handful of these loci have known molecular consequences. The majority of loci are within the non-coding regions of the genome and therefore it is difficult to ascertain how these variants might influence serum urate levels without tangible links to gene expression and / or protein function. We have applied a novel bioinformatic pipeline where we combined population-specific GWAS data with gene expression and genome connectivity information to identify putative causal genes for serum urate associated loci. Overall, we identified 15 novel serum urate loci and show that these loci along with previously identified loci are linked to the expression of 44 genes. We show that some of the variants within these loci have strong predicted regulatory function which can be further tested in functional analyses. This study expands on previous GWAS by identifying further loci implicated in serum urate control and new causal mechanisms supported by gene expression changes.

scholarly journals A novel quantile regression approach for eQTL discovery

2016 ◽  
Author(s):  
Xiaoyu Song ◽  
Gen Li ◽  
Iuliana Ionita-Laza ◽  
Ying Wei
Keyword(s):  
Gene Expression ◽  
Genetic Variation ◽  
Linear Regression ◽  
Genetic Variants ◽  
Molecular Mechanisms ◽  
Association Studies ◽  
Expression Level ◽  
Special Focus ◽  
Genome Wide Association Studies ◽  
Genome Wide

AbstractOver the past decade, there has been a remarkable improvement in our understanding of the role of genetic variation in complex human diseases, especially via genome-wide association studies. However, the underlying molecular mechanisms are still poorly characterized, impending the development of therapeutic interventions. Identifying genetic variants that influence the expression level of a gene, i.e. expression quantitative trait loci (eQTLs), can help us understand how genetic variants influence traits at the molecular level. While most eQTL studies focus on identifying mean effects on gene expression using linear regression, evidence suggests that genetic variation can impact the entire distribution of the expression level. Indeed, several studies have already investigated higher order associations with a special focus on detecting heteroskedasticity. In this paper, we develop a Quantile Rank-score Based Test (QRBT) to identify eQTLs that are associated with the conditional quantile functions of gene expression. We have applied the proposed QRBT to the Genotype-Tissue Expression project, an international tissue bank for studying the relationship between genetic variation and gene expression in human tissues, and found that the proposed QRBT complements the existing methods, and identifies new eQTLs with heterogeneous effects genome-wideacross different quantile levels. Notably, we show that the eQTLs identified by QRBT but missed by linear regression are more likely to be tissue specific, and also associated with greater enrichment in genome-wide significant SNPs from the GWAS catalog. An R package implementing QRBT is available on our website.

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