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 PICALM modulates autophagy activity and tau accumulation

2014 ◽  
Vol 5 (1) ◽  
Author(s):  
Kevin Moreau ◽  
Angeleen Fleming ◽  
Sara Imarisio ◽  
Ana Lopez Ramirez ◽  
Jacob L. Mercer ◽  
...  
Keyword(s):  
Genetic Risk ◽  
Association Studies ◽  
Genome Wide Association Studies ◽  
Transgenic Models ◽  
Autophagosome Formation ◽  
Genome Wide ◽  
Autophagy Pathway ◽  
Autophagy Activity

Abstract Genome-wide association studies have identified several loci associated with Alzheimer’s disease (AD), including proteins involved in endocytic trafficking such as PICALM/CALM (phosphatidylinositol binding clathrin assembly protein). It is unclear how these loci may contribute to AD pathology. Here we show that CALM modulates autophagy and alters clearance of tau, a protein which is a known autophagy substrate and which is causatively linked to AD, both in vitro and in vivo. Furthermore, altered CALM expression exacerbates tau-mediated toxicity in zebrafish transgenic models. CALM influences autophagy by regulating the endocytosis of SNAREs, such as VAMP2, VAMP3 and VAMP8, which have diverse effects on different stages of the autophagy pathway, from autophagosome formation to autophagosome degradation. This study suggests that the AD genetic risk factor CALM modulates autophagy, and this may affect disease in a number of ways including modulation of tau turnover.

scholarly journals Alzheimer's disease-associated P460L mutation in ephrin receptor type A1 (EphA1) leads to dysregulated Rho-GTPase signaling

2021 ◽  
Author(s):  
Yoon Kim ◽  
Gorka Lasso ◽  
Hardik Patel ◽  
Badri Vardarajan ◽  
Ismael Santa-Maria ◽  
...  
Keyword(s):  
Rho Gtpase ◽  
Late Onset ◽  
Association Studies ◽  
Genome Wide Association Studies ◽  
Genome Wide ◽  
The Brain ◽  
Receptor Tyrosine Kinase Family

Recently, late onset AD (LOAD) genome-wide association studies identified EphA1, a member of receptor tyrosine kinase family (RTK) as a disease associated loci. In the follow-up study where 3 independent LOAD cohorts were performed, a P460L coding mutation in EphA1 loci showed a significant association with LOAD. However, the role of EphA1 and P460L mutant EphA1 in AD is not fully understood. We have characterized this mutation biophysically and biochemically. Our structural in silico model and in vitro biochemical analysis demonstrate that EphA1-P460L mutation makes the receptor constitutively active suggesting a gain-of-toxic function leading to chronic EphA1 signaling in the brain. Moreover, we report that the EphA1 P460L variant triggers Rho-GTPase signaling dysregulation that could potentially contribute to spine morphology abnormalities and synaptic dysfunction observed in AD pathology.

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 Implication of sestrin3 in epilepsy and its comorbidities

2020 ◽  
Author(s):  
Francesca Lovisari ◽  
Paolo Roncon ◽  
Marie Soukoupova ◽  
Giovanna Paolone ◽  
Marilyne Labasque ◽  
...  
Keyword(s):  
Brain Injury ◽  
Association Studies ◽  
Acquired Brain Injury ◽  
Genome Wide Association Studies ◽  
Knock Out ◽  
Genome Wide ◽  
Inflammatory Processes ◽  
Anxiety Depression

Abstract Epilepsy is a serious neurological disorder affecting about 1% of the population worldwide. Epilepsy may arise as a result of acquired brain injury, or as a consequence of genetic predisposition. To date, genome-wide association studies and exome sequencing approaches have provided limited insights into the mechanisms of acquired brain injury. We have previously reported a pro-epileptic gene network, which is conserved across species, encoding inflammatory processes and positively regulated by sestrin 3 (SESN3). In this study, we investigated the phenotype of SESN3 knock-out rats in terms of susceptibility to seizures and observed a significant delay in status epilepticus onset in SESN3 knock-out compared to control rats. This finding confirms previous in vitro and in vivo evidence indicating that SESN3 may favor occurrence and/or severity of seizures. We also analyzed the phenotype of SESN3 knock-out rats for common comorbidities of epilepsy, i.e. anxiety, depression, and cognitive impairment. SESN3 knock-out rats proved less anxious compared to control rats in a selection of behavioral tests. Taken together, the present results suggest that SESN3 may regulate mechanisms involved in the pathogenesis of epilepsy and its comorbidities.

scholarly journals A histone acetylome-wide association study of Alzheimer’s disease: neuropathology-associated regulatory variation in the human entorhinal cortex

2017 ◽  
Author(s):  
Sarah J. Marzi ◽  
Teodora Ribarska ◽  
Adam R. Smith ◽  
Eilis Hannon ◽  
Jeremie Poschmann ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Entorhinal Cortex ◽  
Neurodegenerative Disorder ◽  
Late Onset ◽  
Association Studies ◽  
Amyloid Β ◽  
Genomic Variation ◽  
Genome Wide Association Studies ◽  
Genome Wide

AbstractAlzheimer’s disease (AD) is a chronic neurodegenerative disorder characterized by the progressive accumulation of amyloid-β (Aβ) plaques and neurofibrillary tangles in the neocortex. Recent studies have implicated a role for regulatory genomic variation in AD progression, finding widespread evidence for altered DNA methylation associated with neuropathology. To date, however, no study has systematically examined other types of regulatory genomic modifications in AD. In this study, we quantified genome-wide patterns of lysine H3K27 acetylation (H3K27ac) - a robust mark of active enhancers and promoters that is strongly correlated with gene expression and transcription factor binding - in entorhinal cortex samples from AD cases and matched controls (n = 47) using chromatin immunoprecipitation followed by highly parallel sequencing (ChIP-seq). Across ~182,000 robustly detected H3K27ac peak regions, we found widespread acetylomic variation associated with AD neuropathology, identifying 4,162 differential peaks (FDR < 0.05) between AD cases and controls. These differentially acetylated peaks are enriched in disease-specific biological pathways and include regions annotated to multiple genes directly involved in the progression of Aβ and tau pathology (e.g. APP, PSEN1, PSEN2, MAPT), as well as genomic regions containing variants associated with sporadic late-onset AD. This is the first study of variable H3K27ac yet undertaken in AD and the largest study investigating this modification in the entorhinal cortex. In addition to identifying molecular pathways associated with AD neuropathology, we present a framework for genome-wide studies of histone modifications in complex disease, integrating our data with results obtained from genome-wide association studies as well as other epigenetic marks profiled on the same samples.

Migraine: Genetic Variants and Clinical Phenotypes

2019 ◽  
Vol 26 (34) ◽  
pp. 6207-6221 ◽  
Author(s):  
Innocenzo Rainero ◽  
Alessandro Vacca ◽  
Flora Govone ◽  
Annalisa Gai ◽  
Lorenzo Pinessi ◽  
...  
Keyword(s):  
Genetic Variants ◽  
Association Studies ◽  
Mthfr Gene ◽  
Genome Wide Association Studies ◽  
Clinical Phenotypes ◽  
Network Analyses ◽  
Genome Wide ◽  
Genomic Studies ◽  
The Common ◽  
The Relationship

Migraine is a common, chronic neurovascular disorder caused by a complex interaction between genetic and environmental risk factors. In the last two decades, molecular genetics of migraine have been intensively investigated. In a few cases, migraine is transmitted as a monogenic disorder, and the disease phenotype cosegregates with mutations in different genes like CACNA1A, ATP1A2, SCN1A, KCNK18, and NOTCH3. In the common forms of migraine, candidate genes as well as genome-wide association studies have shown that a large number of genetic variants may increase the risk of developing migraine. At present, few studies investigated the genotype-phenotype correlation in patients with migraine. The purpose of this review was to discuss recent studies investigating the relationship between different genetic variants and the clinical characteristics of migraine. Analysis of genotype-phenotype correlations in migraineurs is complicated by several confounding factors and, to date, only polymorphisms of the MTHFR gene have been shown to have an effect on migraine phenotype. Additional genomic studies and network analyses are needed to clarify the complex pathways underlying migraine and its clinical phenotypes.

scholarly journals Asthma-associated genetic variants induce IL33 differential expression through an enhancer-blocking regulatory region

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Ivy Aneas ◽  
Donna C. Decker ◽  
Chanie L. Howard ◽  
Débora R. Sobreira ◽  
Noboru J. Sakabe ◽  
...  
Keyword(s):  
Association Studies ◽  
Regulatory Region ◽  
Airway Epithelial Cells ◽  
Genome Wide Association Studies ◽  
Airway Epithelial ◽  
Allele Specific ◽  
Enhancer Blocking ◽  
Underlying Mechanisms

AbstractGenome-wide association studies (GWAS) have implicated the IL33 locus in asthma, but the underlying mechanisms remain unclear. Here, we identify a 5 kb region within the GWAS-defined segment that acts as an enhancer-blocking element in vivo and in vitro. Chromatin conformation capture showed that this 5 kb region loops to the IL33 promoter, potentially regulating its expression. We show that the asthma-associated single nucleotide polymorphism (SNP) rs1888909, located within the 5 kb region, is associated with IL33 gene expression in human airway epithelial cells and IL-33 protein expression in human plasma, potentially through differential binding of OCT-1 (POU2F1) to the asthma-risk allele. Our data demonstrate that asthma-associated variants at the IL33 locus mediate allele-specific regulatory activity and IL33 expression, providing a mechanism through which a regulatory SNP contributes to genetic risk of asthma.

scholarly journals Age-related late-onset disease heritability patterns and implications for genome-wide association studies

2018 ◽  
Author(s):  
Roman Teo Oliynyk
Keyword(s):  
Old Age ◽  
Cumulative Incidence ◽  
Late Onset ◽  
Association Studies ◽  
Genome Wide Association ◽  
Risk Scores ◽  
Cerebral Stroke ◽  
Genome Wide Association Studies ◽  
Polygenic Risk ◽  
Genome Wide

AbstractBackgroundGenome-wide association studies and other computational biology techniques are gradually discovering the causal gene variants that contribute to late-onset human diseases. After more than a decade of genome-wide association study efforts, these can account for only a fraction of the heritability implied by familial studies, the so-called “missing heritability” problem.MethodsComputer simulations of polygenic late-onset diseases in an aging population have quantified the risk allele frequency decrease at older ages caused by individuals with higher polygenic risk scores becoming ill proportionately earlier. This effect is most prominent for diseases characterized by high cumulative incidence and high heritability, examples of which include Alzheimer’s disease, coronary artery disease, cerebral stroke, and type 2 diabetes.ResultsThe incidence rate for late-onset diseases grows exponentially for decades after early onset ages, guaranteeing that the cohorts used for genome-wide association studies overrepresent older individuals with lower polygenic risk scores, whose disease cases are disproportionately due to environmental causes such as old age itself. This mechanism explains the decline in clinical predictive power with age and the lower discovery power of familial studies of heritability and genome-wide association studies. It also explains the relatively constant-with-age heritability found for late-onset diseases of lower prevalence, exemplified by cancers.ConclusionsFor late-onset polygenic diseases showing high cumulative incidence together with high initial heritability, rather than using relatively old age-matched cohorts, study cohorts combining the youngest possible cases with the oldest possible controls may significantly improve the discovery power of genome-wide association studies.

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.

Genome-wide association studies of Ca and Mn in the seeds of the common bean (Phaseolus vulgaris L.)

Genomics ◽  
2020 ◽  
Vol 112 (6) ◽  
pp. 4536-4546
Author(s):  
Semih Erdogmus ◽  
Duygu Ates ◽  
Seda Nemli ◽  
Bulent Yagmur ◽  
Tansel Kaygisiz Asciogul ◽  
...  
Keyword(s):  
Phaseolus Vulgaris ◽  
Common Bean ◽  
Association Studies ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Phaseolus Vulgaris L ◽  
Genome Wide ◽  
The Common
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