scholarly journals A missense variant in SHARPIN mediates Alzheimer’s disease-specific brain damages

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Jun Young Park ◽  
Dongsoo Lee ◽  
Jang Jae Lee ◽  
Jungsoo Gim ◽  
Tamil Iniyan Gunasekaran ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cortical Thickness ◽  
Association Studies ◽  
Brain Magnetic Resonance Imaging ◽  
Amyloid Β ◽  
Missense Variant ◽  
Hippocampal Volume ◽  
Genome Wide Association Studies ◽  
Increased Risk

AbstractEstablished genetic risk factors for Alzheimer’s disease (AD) account for only a portion of AD heritability. The aim of this study was to identify novel associations between genetic variants and AD-specific brain atrophy. We conducted genome-wide association studies for brain magnetic resonance imaging measures of hippocampal volume and entorhinal cortical thickness in 2643 Koreans meeting the clinical criteria for AD (n = 209), mild cognitive impairment (n = 1449) or normal cognition (n = 985). A missense variant, rs77359862 (R274W), in the SHANK-associated RH Domain Interactor (SHARPIN) gene was associated with entorhinal cortical thickness (p = 5.0 × 10−9) and hippocampal volume (p = 5.1 × 10−12). It revealed an increased risk of developing AD in the mediation analyses. This variant was also associated with amyloid-β accumulation (p = 0.03) and measures of memory (p = 1.0 × 10−4) and executive function (p = 0.04). We also found significant association of other SHARPIN variants with hippocampal volume in the Alzheimer’s Disease Neuroimaging Initiative (rs3417062, p = 4.1 × 10−6) and AddNeuroMed (rs138412600, p = 5.9 × 10−5) cohorts. Further, molecular dynamics simulations and co-immunoprecipitation indicated that the variant significantly reduced the binding of linear ubiquitination assembly complex proteins, SHPARIN and HOIL-1 Interacting Protein (HOIP), altering the downstream NF-κB signaling pathway. These findings suggest that SHARPIN plays an important role in the pathogenesis of AD.

scholarly journals ABCA7 and Pathogenic Pathways of Alzheimer’s Disease

2018 ◽  
Vol 8 (2) ◽  
pp. 27 ◽  
Author(s):  
◽  
◽  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Association Studies ◽  
Amyloid Β ◽  
Current Evidence ◽  
Genome Wide Association Studies ◽  
In Vivo Models ◽  
Peripheral Tissues ◽  
Increased Risk ◽  
The Brain

The ATP-binding cassette (ABC) reporter family functions to regulate the homeostasis of phospholipids and cholesterol in the central nervous system, as well as peripheral tissues. ABCA7 belongs to the A subfamily of ABC transporters, which shares 54% sequence identity with ABCA1. While ABCA7 is expressed in a variety of tissues/organs, including the brain, recent genome-wide association studies (GWAS) have identified ABCA7 gene variants as susceptibility loci for late-onset Alzheimer’s disease (AD). More important, subsequent genome sequencing analyses have revealed that premature termination codon mutations in ABCA7 are associated with the increased risk for AD. Alzheimer’s disease is a progressive neurodegenerative disease and the most common cause of dementia, where the accumulation and deposition of amyloid-β (Aβ) peptides cleaved from amyloid precursor protein (APP) in the brain trigger the pathogenic cascade of the disease. In consistence with human genetic studies, increasing evidence has demonstrated that ABCA7 deficiency exacerbates Aβ pathology using in vitro and in vivo models. While ABCA7 has been shown to mediate phagocytic activity in macrophages, ABCA7 is also involved in the microglial Aβ clearance pathway. Furthermore, ABCA7 deficiency results in accelerated Aβ production, likely by facilitating endocytosis and/or processing of APP. Taken together, current evidence suggests that ABCA7 loss-of-function contributes to AD-related phenotypes through multiple pathways. A better understanding of the function of ABCA7 beyond lipid metabolism in both physiological and pathological conditions becomes increasingly important to explore AD pathogenesis.

scholarly journals Genetic Variability in Molecular Pathways Implicated in Alzheimer's Disease: A Comprehensive Review

2021 ◽  
Vol 13 ◽  
Author(s):  
David Vogrinc ◽  
Katja Goričar ◽  
Vita Dolžan
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Age Of Onset ◽  
Association Studies ◽  
The Elderly ◽  
Gene Clustering ◽  
Molecular Pathways ◽  
Genome Wide Association Studies ◽  
Cellular Processes ◽  
Increased Risk

Alzheimer's disease (AD) is a complex neurodegenerative disease, affecting a significant part of the population. The majority of AD cases occur in the elderly with a typical age of onset of the disease above 65 years. AD presents a major burden for the healthcare system and since population is rapidly aging, the burden of the disease will increase in the future. However, no effective drug treatment for a full-blown disease has been developed to date. The genetic background of AD is extensively studied; numerous genome-wide association studies (GWAS) identified significant genes associated with increased risk of AD development. This review summarizes more than 100 risk loci. Many of them may serve as biomarkers of AD progression, even in the preclinical stage of the disease. Furthermore, we used GWAS data to identify key pathways of AD pathogenesis: cellular processes, metabolic processes, biological regulation, localization, transport, regulation of cellular processes, and neurological system processes. Gene clustering into molecular pathways can provide background for identification of novel molecular targets and may support the development of tailored and personalized treatment of AD.

scholarly journals Pyk2 overexpression in postsynaptic neurons blocks amyloid β1–42-induced synaptotoxicity in microfluidic co-cultures

2020 ◽  
Vol 2 (2) ◽  
Author(s):  
Devrim Kilinc ◽  
Anaïs-Camille Vreulx ◽  
Tiago Mendes ◽  
Amandine Flaig ◽  
Diego Marques-Coelho ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Precursor Protein ◽  
Genetic Risk ◽  
Association Studies ◽  
Amyloid Β ◽  
Precursor Protein ◽  
Genome Wide Association Studies ◽  
Risk Genes ◽  
The Impact

Abstract Recent meta-analyses of genome-wide association studies identified a number of genetic risk factors of Alzheimer’s disease; however, little is known about the mechanisms by which they contribute to the pathological process. As synapse loss is observed at the earliest stage of Alzheimer’s disease, deciphering the impact of Alzheimer’s risk genes on synapse formation and maintenance is of great interest. In this article, we report a microfluidic co-culture device that physically isolates synapses from pre- and postsynaptic neurons and chronically exposes them to toxic amyloid β peptides secreted by model cell lines overexpressing wild-type or mutated (V717I) amyloid precursor protein. Co-culture with cells overexpressing mutated amyloid precursor protein exposed the synapses of primary hippocampal neurons to amyloid β1–42 molecules at nanomolar concentrations and induced a significant decrease in synaptic connectivity, as evidenced by distance-based assignment of postsynaptic puncta to presynaptic puncta. Treating the cells with antibodies that target different forms of amyloid β suggested that low molecular weight oligomers are the likely culprit. As proof of concept, we demonstrate that overexpression of protein tyrosine kinase 2 beta—an Alzheimer’s disease genetic risk factor involved in synaptic plasticity and shown to decrease in Alzheimer’s disease brains at gene expression and protein levels—selectively in postsynaptic neurons is protective against amyloid β1–42-induced synaptotoxicity. In summary, our lab-on-a-chip device provides a physiologically relevant model of Alzheimer’s disease-related synaptotoxicity, optimal for assessing the impact of risk genes in pre- and postsynaptic compartments.

scholarly journals PVRL2 rs6859 Modifies the Effect of Triglyceride on Progression of Mild Cognitive Impairment: The Shanghai Aging Study

2020 ◽  
Author(s):  
Ruru Wang ◽  
Ding Ding ◽  
Abuduaili Atibaike ◽  
Jianxiong Xi ◽  
Qianhua Zhao ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Impairment ◽  
Mild Cognitive Impairment ◽  
Cox Model ◽  
Association Studies ◽  
Interactive Effect ◽  
Genome Wide Association Studies ◽  
Increased Risk ◽  
Aging Study

Abstract Background Mild cognitive impairment (MCI) is an intermediate stage between normal cognition and Alzheimer’s disease (AD). Genome-wide association studies (GWAS) have identified many AD-risk variants and indicated the important role of lipid metabolism pathway in AD progression. This study aimed to investigate the effects of triglyceride (TG) and genetic risk factors on progression from MCI to AD (MCI-AD progression).Methods The current study sample comprised of 305 MCI subjects aged 50 and over who were prospectively followed up for average 4.5 years in a sub-cohort of the Shanghai Aging Study. A consensus diagnosis of incident AD was conducted according to Diagnostic and Statistical Manual of Mental Disorders-IV and the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer’s Disease and Related Disorders Association criteria. Fasting blood samples were obtained at baseline for analyzing serum TG. Single nucleotide polymorphisms (SNPs) genotyping was performed using a MassARRAY system. The effect of TG, genetic variants and their interaction on MCI-AD progression were analyzed using Cox proportional hazards regression model.Results During a mean (±SD) follow-up period of 4.5±1.3 y, 58 subjects developed incident AD. The SNP, rs6859 in the Poliovirus Receptor–Related 2 (PVRL2) gene, was significantly associated with incident AD (false discovery rate (FDR)-adjusted P = 0.018). In multivariate cox model, the PVRL2 rs6859 AG, AA and AG+AA genotypes were associated with significantly increased incident AD, compared with the GG genotype (hazard ratio [HR] = 2.29, P = 0.029, and HR = 2.92, P = 0.013, and HR = 2.47, P =0.012, respectively). In PVRL2 rs6859 AG/AA carriers, higher ln TG was significantly associated with increased risk of incident AD (adjusted HR =2.64, P = 0.034). Ln TG and PVRL2 rs6859 had interactive effect on the MCI-AD progression (P Ln TG × rs6859 = 0.001). Conclusion The present study indicated that PVRL2 rs6859 modified the effect of TG on MCI-AD progression. Precision prevention in MCI population based on genetic information should be considered to avoid progression to AD.

scholarly journals Multi-trait association studies discover pleiotropic loci between Alzheimer's disease and cardiometabolic traits

2020 ◽  
Author(s):  
William Paul Bone ◽  
Katherine M Siewert ◽  
Anupama Jha ◽  
Derek Klarin ◽  
Scott M Damrauer ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Association Studies ◽  
Low Frequency ◽  
Tissue Expression ◽  
Genome Wide Association Studies ◽  
Frequency Coding ◽  
Increased Risk ◽  
Hypertensive Drug ◽  
Cardiometabolic Traits

Identification of genetic risk factors that are shared between Alzheimer's disease (AD) and other traits, i.e., pleiotropy, can help improve our understanding of the etiology of AD and potentially detect new therapeutic targets. Motivated by previous epidemiological correlations observed between cardiometabolic traits and AD, we performed a set of bivariate genome-wide association studies coupled with colocalization analysis to identify loci that are shared between AD and eleven cardiometabolic traits. We identified three previously unreported pleiotropic trait associations at known AD loci as well as four novel pleiotropic loci. One associated locus was tagged by a low-frequency coding variant in the gene DOCK4 and is potentially implicated in its alternative splicing. Statistical colocalization with expression quantitative trait loci identified by the Genotype-Tissue Expression (GTEx) project identified additional candidate genes, including ACE, the target of the hypertensive drug class of ACE-inhibitors. We found that the allele associated with decreased ACE expression in brain tissue was also associated with increased risk of AD, providing human genetic evidence of a potential increase in AD risk from use of an established anti-hypertensive therapeutic. Overall, our results support a complex genetic relationship between AD and these cardiometabolic traits, and the candidate causal genes identified suggest that blood pressure and immune response play a role in the pleiotropy between these traits.

Understanding the function of ABCA7 in Alzheimer's disease

2015 ◽  
Vol 43 (5) ◽  
pp. 920-923 ◽  
Author(s):  
Hongyun Li ◽  
Tim Karl ◽  
Brett Garner
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Association Studies ◽  
Chinese Hamster Ovary Cells ◽  
Amyloid Β ◽  
Mutant Form ◽  
Genome Wide Association Studies ◽  
App Processing ◽  
The Brain

ATP-binding cassette transporter A7 (ABCA7) is highly expressed in the brain. Recent genome-wide association studies (GWAS) identify ABCA7 single nt polymorphisms (SNPs) that increase Alzheimer's disease (AD) risk. It is now important to understand the true function of ABCA7 in the AD context. We have begun to address this using in vitro and in vivo AD models. Our initial studies showed that transient overexpression of ABCA7 in Chinese hamster ovary cells stably expressing human amyloid precursor protein (APP) resulted in an approximate 50% inhibition in the production of the AD-related amyloid-β (Aβ) peptide as compared with mock-transfected cells. This increased ABCA7 expression was also associated with alterations in other markers of APP processing and an accumulation of cellular APP. To probe for a function of ABCA7 in vivo, we crossed Abca7−/− mice with J20 mice, an amyloidogenic transgenic AD mouse model [B6.Cg-Tg(PDGFB-APPSwInd)20Lms/J] expressing a mutant form of human APP bearing both the Swedish (K670N/M671L) and Indiana (V717F) familial AD mutations. We found that ABCA7 loss doubled insoluble Aβ levels and amyloid plaques in the brain. This did not appear to be related to changes in APP processing (C-terminal fragment analysis), which led us to assess other mechanism by which ABCA7 may modulate Aβ homoeostasis. As we have shown that microglia express high levels of ABCA7, we examined a role for ABCA7 in the phagocytic clearance of Aβ. Our data indicated that the capacity for bone marrow-derived macrophages derived from Abca7−/− mice to phagocytose Aβ was reduced by 51% compared with wild-type (WT) mice. This suggests ABCA7 plays a role in the regulation of Aβ homoeostasis in the brain and that this may be related to Aβ clearance by microglia.

scholarly journals Possible Role of Activin in the Adiponectin Paradox-Induced Progress of Alzheimer’s Disease

2021 ◽  
pp. 1-8
Author(s):  
Makoto Hashimoto ◽  
Gilbert Ho ◽  
Shuei Sugama ◽  
Takato Takenouchi ◽  
Masaaki Waragai ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Transforming Growth Factor ◽  
Association Studies ◽  
Meta Analysis ◽  
Amyloid Β ◽  
Activin A ◽  
Antagonistic Pleiotropy ◽  
Type I ◽  
Genome Wide Association Studies

Accumulating evidence suggests that the adiponectin (APN) paradox might be involved in promoting aging-associated chronic diseases such as Alzheimer’s disease (AD). In human brain, APN regulation of the evolvability of amyloidogenic proteins (APs), including amyloid-β (Aβ) and tau, in developmental/reproductive stages, might be paradoxically manifest as APN stimulation of AD through antagonistic pleiotropy in aging. The unique mechanisms underlying APN activity remain unclear, a better understanding of which might provide clues for AD therapy. In this paper, we discuss the possible relevance of activin, a member of transforming growth factor β (TGFβ) superfamily of peptides, to antagonistic pleiotropy effects of APN. Notably, activin, a multiple regulator of cell proliferation and differentiation, as well as an endocrine modulator in reproduction and an organizer in early development, might promote aging-associated disorders, such as inflammation and cancer. Indeed, serum activin, but not serum TGFβ increases during aging. Also, activin/TGFβ signal through type II and type I receptors, both of which are transmembrane serine/threonine kinases, and the serine/threonine phosphorylation of APs, including Aβ 42 serine 8 and αS serine 129, may confer pathological significance in neurodegenerative diseases. Moreover, activin expression is induced by APN in monocytes and hepatocytes, suggesting that activin might be situated downstream of the APN paradox. Finally, a meta-analysis of genome-wide association studies demonstrated that two SNPs relevant to the activin/TGFβ receptor signaling pathways conferred risk for major aging-associated disease. Collectively, activin might be involved in the APN paradox of AD and could be a significant therapeutic target.

scholarly journals Association between polygenic risk score of Alzheimer’s disease and plasma phosphorylated tau in individuals from the Alzheimer’s Disease Neuroimaging Initiative

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Anna Zettergren ◽  
◽  
Jodie Lord ◽  
Nicholas J. Ashton ◽  
Andrea L. Benedet ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Association Studies ◽  
Amyloid Β ◽  
Total Sample ◽  
Risk Scores ◽  
Polygenic Risk Score ◽  
Genome Wide Association Studies ◽  
Tau Pathology ◽  
Polygenic Risk

Abstract Background Recent studies suggest that plasma phosphorylated tau181 (p-tau181) is a highly specific biomarker for Alzheimer’s disease (AD)-related tau pathology. It has great potential for the diagnostic and prognostic evaluation of AD, since it identifies AD with the same accuracy as tau PET and CSF p-tau181 and predicts the development of AD dementia in cognitively unimpaired (CU) individuals and in those with mild cognitive impairment (MCI). Plasma p-tau181 may also be used as a biomarker in studies exploring disease pathogenesis, such as genetic or environmental risk factors for AD-type tau pathology. The aim of the present study was to investigate the relation between polygenic risk scores (PRSs) for AD and plasma p-tau181. Methods Data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) was used to examine the relation between AD PRSs, constructed based on findings in recent genome-wide association studies, and plasma p-tau181, using linear regression models. Analyses were performed in the total sample (n = 818), after stratification on diagnostic status (CU (n = 236), MCI (n = 434), AD dementia (n = 148)), and after stratification on Aβ pathology status (Aβ positives (n = 322), Aβ negatives (n = 409)). Results Associations between plasma p-tau181 and APOE PRSs (p = 3e−18–7e−15) and non-APOE PRSs (p = 3e−4–0.03) were seen in the total sample. The APOE PRSs were associated with plasma p-tau181 in all diagnostic groups (CU, MCI, and AD dementia), while the non-APOE PRSs were associated only in the MCI group. The APOE PRSs showed similar results in amyloid-β (Aβ)-positive and negative individuals (p = 5e−5–1e−3), while the non-APOE PRSs were associated with plasma p-tau181 in Aβ positives only (p = 0.02). Conclusions Polygenic risk for AD including APOE was found to associate with plasma p-tau181 independent of diagnostic and Aβ pathology status, while polygenic risk for AD beyond APOE was associated with plasma p-tau181 only in MCI and Aβ-positive individuals. These results extend the knowledge about the relation between genetic risk for AD and p-tau181, and further support the usefulness of plasma p-tau181 as a biomarker of AD.

Genetically Predicted Coffee Consumption and Risk of Alzheimer’s Disease and Stroke

2021 ◽  
Vol 83 (4) ◽  
pp. 1815-1823
Author(s):  
Zhizhong Zhang ◽  
Mengmeng Wang ◽  
Shuai Yuan ◽  
Huan Cai ◽  
Shuang-Gen Zhu ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Stroke Risk ◽  
Association Studies ◽  
Coffee Consumption ◽  
Genome Wide Association Studies ◽  
Biological Mechanisms ◽  
Genome Wide ◽  
Level Data ◽  
Increased Risk

Background: Observational studies have reported that coffee consumption was associated with Alzheimer’s disease (AD) and stroke risk. However, the results are inconclusive. Objective: We aimed to evaluate whether genetically predicted coffee consumption is associated with AD and stroke using Mendelian randomization (MR) design. Methods: Summary-level data for AD (n = 54,162), ischemic stroke (n = 440,328), and intracerebral hemorrhage (ICH, n = 3,026) were adopted from publicly available databases. Summary-level data for coffee consumption were obtained from two genome-wide association studies, comprising up to 375,833 subjects. Results: Genetically predicted coffee consumption (cups/day) was associated with an increased risk of AD (OR = 1.26, 95%CI = 1.05–1.51). Moreover, genetically predicted 50%increase of coffee consumption was associated with an increased risk of ICH (OR: 2.27, 95%CI: 1.08–4.78) but a decreased risk of small vessel stroke (OR: 0.71, 95%CI: 0.51–0.996). Estimate for AD and ICH in FinnGen consortium is directionally consistent. Combined analysis of different databases further confirmed that genetically predicted coffee consumption was associated with an increased risk of AD and ICH. In the multivariable MR analysis, genetically predicted coffee consumption retained a stable effect with AD and ICH when adjusting for smoking (p < 0.05), while the association with AD attenuated when adjusting for alcohol use. Conclusion: Our results indicate that genetically predicted coffee consumption may be associated with an increased risk of AD and ICH. The underlying biological mechanisms warrant further study.

scholarly journals Multi-trait association studies discover pleiotropic loci between Alzheimer’s disease and cardiometabolic traits

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
William P. Bone ◽  
◽  
Katherine M. Siewert ◽  
Anupama Jha ◽  
Derek Klarin ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Association Studies ◽  
Low Frequency ◽  
Tissue Expression ◽  
Genome Wide Association Studies ◽  
Frequency Coding ◽  
Increased Risk ◽  
Causal Genes ◽  
Cardiometabolic Traits

Abstract Background Identification of genetic risk factors that are shared between Alzheimer’s disease (AD) and other traits, i.e., pleiotropy, can help improve our understanding of the etiology of AD and potentially detect new therapeutic targets. Previous epidemiological correlations observed between cardiometabolic traits and AD led us to assess the pleiotropy between these traits. Methods We performed a set of bivariate genome-wide association studies coupled with colocalization analysis to identify loci that are shared between AD and eleven cardiometabolic traits. For each of these loci, we performed colocalization with Genotype-Tissue Expression (GTEx) project expression quantitative trait loci (eQTL) to identify candidate causal genes. Results We identified three previously unreported pleiotropic trait associations at known AD loci as well as four novel pleiotropic loci. One associated locus was tagged by a low-frequency coding variant in the gene DOCK4 and is potentially implicated in its alternative splicing. Colocalization with GTEx eQTL data identified additional candidate genes for the loci we detected, including ACE, the target of the hypertensive drug class of ACE inhibitors. We found that the allele associated with decreased ACE expression in brain tissue was also associated with increased risk of AD, providing human genetic evidence of a potential increase in AD risk from use of an established anti-hypertensive therapeutic. Conclusion Our results support a complex genetic relationship between AD and these cardiometabolic traits, and the candidate causal genes identified suggest that blood pressure and immune response play a role in the pleiotropy between these traits.

Sign in / Sign up

Export Citation Format

Share Document