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1.
Alzheimers Dement ; 17 Suppl 12: e058171, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34971096

RESUMO

BACKGROUND: The Apolipoprotein E ε4 (APOE ε4) haplotype is the strongest genetic risk factor for late-onset Alzheimer's disease (AD). The Translocase of Outer Mitochondrial Membrane-40 (TOMM40) gene maintains cellular bioenergetics, which is disrupted in AD. TOMM40 rs2075650 ('650) G vs. A carriage is consistently related to neural and cognitive outcomes, but it is unclear if and how it interacts with APOE. METHOD: We examined 21 orthogonal neural networks among 8,222 middle-aged to aged participants in the UK Biobank cohort. ANOVA and multiple linear regression tested main effects and interactions with APOE and TOMM40 '650 genotypes, and if age and sex acted as moderators RESULT: APOE ε4 was associated with less strength in multiple networks, while '650 G vs. A carriage was related to more language comprehension network strength. In APOE ε4 carriers, '650 G-carriage led to less network strength with increasing age, while in non G-carriers this was only seen in women but not men. CONCLUSION: TOMM40 may shift what happens to network activity in aging APOE ε4 carriers depending on sex.

2.
Alzheimers Dement ; 17 Suppl 2: e058724, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34971187

RESUMO

BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, robust microgliosis, neuroinflammation, and neuronal loss. Genome-wide association studies highlighted a prominent role for microglia in late-onset AD (LOAD). Specifically, inositol polyphosphate-5-phosphatase (INPP5D) is selectively expressed in brain microglia and one of its common intronic variants (rs35349669; OR=1.08, 95%CI=1.06-1.11) has been reported to be associated with increased risk of LOAD. INPP5D is linked to the triggering receptor expressed on myeloid cells 2 (TREM2) signaling, but little is known about the function of INPP5D in microglia and how INPP5D regulates TREM2-related AD pathogenesis. Therefore, we aim to understand the role of INPP5D in microglia and AD pathology. METHOD: We performed differential gene expression analysis to investigate INPP5D expression in LOAD and its association with plaque density using transcriptomic (RNA-Seq) data from the Accelerating Medicines Partnership for Alzheimer's Disease (AMP-AD) cohort. We also performed quantitative real-time PCR, immunoblotting, and immunofluorescence assays to assess INPP5D expression and microglial markers in the 5xFAD amyloid mouse model with INPP5D deficiency. Using the INPP5D knockout animal crossed with the 5xFAD, we perform the behavioral assays and IHC staining to reveal how the INPP5D regulates the amyloid pathology. RESULT: INPP5D gene expression was upregulated in LOAD and positively correlated with the amyloid plaque density. Inpp5d expression increased along with the disease progression in the 5xFAD mice, and is selectively expressed in plaque-associated microglia. Also, Inpp5d inhibition mitigated the plaque burdens in the 5xFAD mice and further protected against behavioral deficits induced by amyloid pathology. CONCLUSION: Our findings show that INPP5D expression increases throughout the AD progression and is predominantly in the plaque-associated microglia. Importantly, inhibited INPP5D expression reduces amyloid pathology, highlighting INPP5D as a potential therapeutic target.

3.
Alzheimers Dement ; 17 Suppl 2: e058740, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34971198

RESUMO

BACKGROUND: Alzheimer's disease (AD) and other neurodegenerative diseases are typified by a robust microglial-mediated immune response. Genetic studies have demonstrated that variants in microglial genes are linked to risk for AD. Phospholipase C gamma 2 (PLCG2), whose variants confer altered risk for AD, is a critical signaling element for various immune receptors and is a key regulatory hub gene for immune signaling. To date, it is known that PLCG2 might be important in AD due to the pervious findings that a hypermorphic variant in PLCG2, rs72824905, is protective against AD risk. However, the role of PLCG2 has not yet been comprehensively explored. We believe that genetic mouse models are needed to further clarify the role of PLCG2 in plaque-associated microglia and to determine whether decreased PLCG2 expression in plaque-associated microglia favors disease exacerbation or attenuation. METHOD: To investigate the impact of reduced PLCG2 gene expression on microglia biology and disease pathology, we have generated PLCG2 inactivation mice, all crossed onto the 5XFAD amyloidogenic murine model of AD. RESULT: We provide data demonstrating that in individuals with AD, there is increased expression of PLCG2 in the brain, a finding that is recapitulated in 5XFAD mice. We show that reduced PLCG2 gene expression program microglial phenotypes in 5XFAD mice, affect plaque pathology, and drive distinct transcriptional phenotypes of microglia in the presence of amyloid pathology. Analysis of plaque pathology revealed that 5XFAD PLCG2 inactivation mice have elevated plaque burden. Compared to 5XFAD mice, behavioral analysis of 5XFAD with PLCG2 inactivation mice demonstrated an impaired performance in the Y maze assay, reflecting impaired cognitive decline. Our data suggest that the inactivation of PLCG2 had accelerated and exacerbated disease-related pathology. CONCLUSION: Together, our findings provide evidence that PLCG2 plays an important role in AD pathophysiology, indicating PLCG2 as a potential new therapeutic target for AD.

4.
Transl Psychiatry ; 11(1): 590, 2021 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-34785643

RESUMO

Established 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-ß 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.

5.
Neurobiol Aging ; 109: 158-165, 2021 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-34740077

RESUMO

The Apolipoprotein E ε4 (APOE ε4) haplotype is the strongest genetic risk factor for late-onset Alzheimer's disease (AD). The Translocase of Outer Mitochondrial Membrane-40 (TOMM40) gene maintains cellular bioenergetics, which is disrupted in AD. TOMM40 rs2075650 ('650) G versus A carriage is consistently related to neural and cognitive outcomes, but it is unclear if and how it interacts with APOE. We examined 21 orthogonal neural networks among 8,222 middle-aged to aged participants in the UK Biobank cohort. ANOVA and multiple linear regression tested main effects and interactions with APOE and TOMM40 '650 genotypes, and if age and sex acted as moderators. APOE ε4 was associated with less strength in multiple networks, while '650 G versus A carriage was related to more language comprehension network strength. In APOE ε4 carriers, '650 G-carriage led to less network strength with increasing age, while in non-G-carriers this was only seen in women but not men. TOMM40 may shift what happens to network activity in aging APOE ε4 carriers depending on sex.

6.
Alzheimers Dement ; 2021 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-34757660

RESUMO

Metabolites, the biochemical products of the cellular process, can be used to measure alterations in biochemical pathways related to the pathogenesis of Alzheimer's disease (AD). However, the relationships between systemic abnormalities in metabolism and the pathogenesis of AD are poorly understood. In this study, we aim to identify AD-specific metabolomic changes and their potential upstream genetic and transcriptional regulators through an integrative systems biology framework for analyzing genetic, transcriptomic, metabolomic, and proteomic data in AD. Metabolite co-expression network analysis of the blood metabolomic data in the Alzheimer's Disease Neuroimaging Initiative (ADNI) shows short-chain acylcarnitines/amino acids and medium/long-chain acylcarnitines are most associated with AD clinical outcomes, including episodic memory scores and disease severity. Integration of the gene expression data in both the blood from the ADNI and the brain from the Accelerating Medicines Partnership Alzheimer's Disease (AMP-AD) program reveals ABCA1 and CPT1A are involved in the regulation of acylcarnitines and amino acids in AD. Gene co-expression network analysis of the AMP-AD brain RNA-seq data suggests the CPT1A- and ABCA1-centered subnetworks are associated with neuronal system and immune response, respectively. Increased ABCA1 gene expression and adiponectin protein, a regulator of ABCA1, correspond to decreased short-chain acylcarnitines and amines in AD in the ADNI. In summary, our integrated analysis of large-scale multiomics data in AD systematically identifies novel metabolites and their potential regulators in AD and the findings pave a way for not only developing sensitive and specific diagnostic biomarkers for AD but also identifying novel molecular mechanisms of AD pathogenesis.

7.
Alzheimers Res Ther ; 13(1): 183, 2021 11 03.
Artigo em Inglês | MEDLINE | ID: mdl-34732252

RESUMO

BACKGROUND: The interaction between the brain and periphery might play a crucial role in the development of Alzheimer's disease (AD). METHODS: Using blood transcriptomic profile data from two independent AD cohorts, we performed expression quantitative trait locus (cis-eQTL) analysis of 29 significant genetic loci from a recent large-scale genome-wide association study to investigate the effects of the AD genetic variants on gene expression levels and identify their potential target genes. We then performed differential gene expression analysis of identified AD target genes and linear regression analysis to evaluate the association of differentially expressed genes with neuroimaging biomarkers. RESULTS: A cis-eQTL analysis identified and replicated significant associations in seven genes (APH1B, BIN1, FCER1G, GATS, MS4A6A, RABEP1, TRIM4). APH1B expression levels in the blood increased in AD and were associated with entorhinal cortical thickness and global cortical amyloid-ß deposition. CONCLUSION: An integrative analysis of genetics, blood-based transcriptomic profiles, and imaging biomarkers suggests that APH1B expression levels in the blood might play a role in the pathogenesis of AD.


Assuntos
Doença de Alzheimer , Precursor de Proteína beta-Amiloide , Endopeptidases , Proteínas de Membrana , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Precursor de Proteína beta-Amiloide/metabolismo , Atrofia/patologia , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Endopeptidases/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Proteínas de Membrana/genética , Transcriptoma
8.
Alzheimers Res Ther ; 13(1): 164, 2021 10 05.
Artigo em Inglês | MEDLINE | ID: mdl-34610832

RESUMO

BACKGROUND: Accumulating evidence suggests that BMI1 confers protective effects against Alzheimer's disease (AD). However, the mechanism remains elusive. Based on recent pathophysiological evidence, we sought for the first time to identify genetic variants in BMI1 as associated with AD biomarkers, including amyloid-ß. METHODS: We used genetic, longitudinal cognition, and cerebrospinal fluid (CSF) biomarker data from participants in the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort (N = 1565). First, we performed a gene-based association analysis of common single nucleotide polymorphisms (SNPs) (minor allele frequency (MAF) > 5%) located within ± 20 kb of the gene boundary of BMI1, an optimal width for including potential regulatory SNPs in the 5' and 3' untranslated regions (UTR) of BMI1, with CSF Aß1-42 levels. Second, we performed cross-sectional and longitudinal association analyses of SNPs in BMI1 with cognitive performance using linear and mixed-effects models. We replicated association of SNPs in BMI1 with cognitive performance in an independent cohort (N=1084), Religious Orders Study and the Rush Memory and Aging Project (ROS/MAP). RESULTS: Gene-based genetic association analysis showed that BMI1 was significantly associated with CSF Aß1-42 levels after adjusting for multiple testing using permutation (permutation-corrected p value=0.005). rs17415557 in BMI1 showed the most significant association with CSF Aß1-42 levels. Participants with minor alleles of rs17415557 have increased CSF Aß1-42 levels compared to those with no minor alleles. Further analysis identified and replicated the minor allele of rs17415557 as being significantly associated with slower cognitive decline rates in AD. CONCLUSIONS: Our findings provide fundamental evidence that BMI1 rs17415557 may serve as a protective mechanism related to AD pathogenesis, which supports the results of previous studies linking BMI1 to protection against AD.


Assuntos
Doença de Alzheimer , Disfunção Cognitiva , Doença de Alzheimer/complicações , Doença de Alzheimer/genética , Peptídeos beta-Amiloides , Disfunção Cognitiva/genética , Estudos Transversais , Humanos , Complexo Repressor Polycomb 1 , Proteínas tau
9.
Brain ; 2021 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-34613391

RESUMO

Occupational attainment, which represents middle-age cognitive activities, is a known proxy marker of cognitive reserve for Alzheimer's disease. Previous genome-wide association studies (GWAS) have identified numerous genetic variants and revealed the genetic architecture of educational attainment, another marker of cognitive reserve. However, the genetic architecture and heritability for occupational attainment remain elusive. We performed a large-scale GWAS of occupational attainment with 248,847 European individuals from the UK Biobank using the proportional odds logistic mixed model method. In this analysis, we defined occupational attainment using the classified job levels formulated in the UK Standard Occupational Classification system considering the individual professional skill and academic level. We identified 30 significant loci (P < 5 × 10-8); 12 were novel variants, unassociated with other traits. Among them, four lead variants were associated with genes expressed in brain tissues by expression quantitative trait loci mapping from 10 brain regions: rs13002946, rs3741368, rs11654986, and rs1627527. The single nucleotide polymorphism (SNP)-based heritability was estimated to be 8.5% (s.e. = 0.004) and partitioned heritability was enriched in the central nervous system and brain tissues. Genetic correlation analysis showed shared genetic backgrounds between occupational attainment and multiple traits, including education, intelligence, leisure activities, life satisfaction, and neuropsychiatric disorders. In two-sample Mendelian randomization (MR) analysis, we demonstrated that high occupation levels were associated with reduced risk for Alzheimer's disease (OR = 0.78, 95% CI = 0.65-0.92 in inverse variance weighted (IVW) method; OR = 0.73, 95% CI = 0.57-0.92 in the weighted median (WM) method). This causal relationship between occupational attainment and Alzheimer's disease was robust in additional sensitivity analysis that excluded potentially pleiotropic SNPs (OR = 0.72, 95% CI = 0.57-0.91 in the IVW method; OR = 0.72, 95% CI = 0.53-0.97 in the WM method). Multivariable MR confirmed that occupational attainment had an independent effect on the risk for Alzheimer's disease even after taking educational attainment into account (OR = 0.72, 95% CI = 0.54-0.95 in the IVW method; OR = 0.68, 95% CI = 0.48-0.97 in the WM method). Overall, our analyses provide insights into the genetic architecture of occupational attainment and demonstrate that occupational attainment is a potential causal protective factor for Alzheimer's disease as a proxy marker of cognitive reserve.

10.
Clin Epigenetics ; 13(1): 191, 2021 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-34654479

RESUMO

BACKGROUND: Identifying biomarkers associated with Alzheimer's disease (AD) progression may enable patient enrichment and improve clinical trial designs. Epigenome-wide association studies have revealed correlations between DNA methylation at cytosine-phosphate-guanine (CpG) sites and AD pathology and diagnosis. Here, we report relationships between peripheral blood DNA methylation profiles measured using Infinium® MethylationEPIC BeadChip and AD progression in participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort. RESULTS: The rate of cognitive decline from initial DNA sampling visit to subsequent visits was estimated by the slopes of the modified Preclinical Alzheimer Cognitive Composite (mPACC; mPACCdigit and mPACCtrailsB) and Clinical Dementia Rating Scale Sum of Boxes (CDR-SB) plots using robust linear regression in cognitively normal (CN) participants and patients with mild cognitive impairment (MCI), respectively. In addition, diagnosis conversion status was assessed using a dichotomized endpoint. Two CpG sites were significantly associated with the slope of mPACC in CN participants (P < 5.79 × 10-8 [Bonferroni correction threshold]); cg00386386 was associated with the slope of mPACCdigit, and cg09422696 annotated to RP11-661A12.5 was associated with the slope of CDR-SB. No significant CpG sites associated with diagnosis conversion status were identified. Genes involved in cognition and learning were enriched. A total of 19, 13, and 5 differentially methylated regions (DMRs) associated with the slopes of mPACCtrailsB, mPACCdigit, and CDR-SB, respectively, were identified by both comb-p and DMRcate algorithms; these included DMRs annotated to HOXA4. Furthermore, 5 and 19 DMRs were associated with conversion status in CN and MCI participants, respectively. The most significant DMR was annotated to the AD-associated gene PM20D1 (chr1: 205,818,956 to 205,820,014 [13 probes], Sidak-corrected P = 7.74 × 10-24), which was associated with both the slope of CDR-SB and the MCI conversion status. CONCLUSION: Candidate CpG sites and regions in peripheral blood were identified as associated with the rate of cognitive decline in participants in the ADNI cohort. While we did not identify a single CpG site with sufficient clinical utility to be used by itself due to the observed effect size, a biosignature composed of DNA methylation changes may have utility as a prognostic biomarker for AD progression.

11.
Int J Mol Sci ; 22(18)2021 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-34576031

RESUMO

TREM2 is among the most well-known Alzheimer's disease (AD) risk genes; however, the functional roles of its AD-associated variants remain to be elucidated, and most known risk alleles are low-frequency variants whose investigation is challenging. Here, we utilized a splicing-guided aggregation method in which multiple low-frequency TREM2 variants were bundled together to investigate the functional impact of those variants on alternative splicing in AD. We analyzed whole genome sequencing (WGS) and RNA-seq data generated from cognitively normal elderly controls (CN) and AD patients in two independent cohorts, representing three regions in the frontal lobe of the human brain: the dorsolateral prefrontal cortex (CN = 213 and AD = 376), frontal pole (CN = 72 and AD = 175), and inferior frontal (CN = 63 and AD = 157). We observed an exon skipping event in the second exon of TREM2, with that exon tending to be more frequently skipped (p = 0.0012) in individuals having at least one low-frequency variant that caused loss-of-function for a splicing regulatory element. In addition, genes differentially expressed between AD patients with high vs. low skipping of the second exon (i.e., loss of a TREM2 functional domain) were significantly enriched in immune-related pathways. Our splicing-guided aggregation method thus provides new insight into the regulation of alternative splicing of the second exon of TREM2 by low-frequency variants and could be a useful tool for further exploring the potential molecular mechanisms of multiple, disease-associated, low-frequency variants.


Assuntos
Processamento Alternativo/genética , Doença de Alzheimer/genética , Predisposição Genética para Doença , Glicoproteínas de Membrana/genética , Receptores Imunológicos/genética , Idoso , Doença de Alzheimer/patologia , Encéfalo/metabolismo , Encéfalo/patologia , Éxons/genética , Feminino , Frequência do Gene/genética , Variação Genética/genética , Humanos , Masculino , Splicing de RNA/genética , RNA-Seq , Sequências Reguladoras de Ácido Nucleico/genética , Sequenciamento Completo do Genoma
12.
Transl Neurodegener ; 10(1): 32, 2021 08 31.
Artigo em Inglês | MEDLINE | ID: mdl-34465370

RESUMO

BACKGROUND: The combinatorial effect of multiple genetic factors calculated as a polygenic risk score (PRS) has been studied to predict disease progression to Alzheimer's disease (AD) from mild cognitive impairment (MCI). Previous studies have investigated the performance of PRS in the prediction of disease progression to AD by including and excluding single nucleotide polymorphisms within the region surrounding the APOE gene. These studies may have missed the APOE genotype-specific predictability of PRS for disease progression to AD. METHODS: We analyzed 732 MCI from the Alzheimer's Disease Neuroimaging Initiative cohort, including those who progressed to AD within 5 years post-baseline (n = 270) and remained stable as MCI (n = 462). The predictability of PRS including and excluding the APOE region (PRS+APOE and PRS-APOE) on the conversion to AD and its interaction with the APOE ε4 carrier status were assessed using Cox regression analyses. RESULTS: PRS+APOE (hazard ratio [HR] 1.468, 95% CI 1.335-1.615) and PRS-APOE (HR 1.293, 95% CI 1.157-1.445) were both associated with a significantly increased risk of MCI progression to dementia. The interaction between PRS+APOE and APOE ε4 carrier status was significant with a P-value of 0.0378. The association of PRSs with the progression risk was stronger in APOE ε4 non-carriers (PRS+APOE: HR 1.710, 95% CI 1.244-2.351; PRS-APOE: HR 1.429, 95% CI 1.182-1.728) than in APOE ε4 carriers (PRS+APOE: HR 1.167, 95% CI 1.005-1.355; PRS-APOE: HR 1.172, 95% CI 1.020-1.346). CONCLUSIONS: PRS could predict the conversion of MCI to dementia with a stronger association in APOE ε4 non-carriers than APOE ε4 carriers. This indicates PRS as a potential genetic predictor particularly for MCI with no APOE ε4 alleles.

14.
Brain Commun ; 3(3): fcab139, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34396103

RESUMO

Metabolomics in the Alzheimer's Disease Neuroimaging Initiative cohort provides a powerful tool for mapping biochemical changes in Alzheimer's disease, and a unique opportunity to learn about the association between circulating blood metabolites and brain amyloid-ß deposition in Alzheimer's disease. We examined 140 serum metabolites and their associations with brain amyloid-ß deposition, cognition and conversion from mild cognitive impairment to Alzheimer's disease in the Alzheimer's Disease Neuroimaging Initiative. Processed [18F] Florbetapir PET images were used to perform a voxel-wise statistical analysis of the effect of metabolite levels on amyloid-ß accumulation across the whole brain. We performed a multivariable regression analysis using age, sex, body mass index, apolipoprotein E ε4 status and study phase as covariates. We identified nine metabolites as significantly associated with amyloid-ß deposition after multiple comparison correction. Higher levels of one acylcarnitine (C3; propionylcarnitine) and one biogenic amine (kynurenine) were associated with decreased amyloid-ß accumulation and higher memory scores. However, higher levels of seven phosphatidylcholines (lysoPC a C18:2, PC aa C42:0, PC ae C42:3, PC ae C44:3, PC ae C44:4, PC ae C44:5 and PC ae C44:6) were associated with increased brain amyloid-ß deposition. In addition, higher levels of PC ae C44:4 were significantly associated with lower memory and executive function scores and conversion from mild cognitive impairment to Alzheimer's disease dementia. Our findings suggest that dysregulation of peripheral phosphatidylcholine metabolism is associated with earlier pathological changes noted in Alzheimer's disease as measured by brain amyloid-ß deposition as well as later clinical features including changes in memory and executive functioning. Perturbations in phosphatidylcholine metabolism may point to issues with membrane restructuring leading to the accumulation of amyloid-ß in the brain. Additional studies are needed to explore whether these metabolites play a causal role in the pathogenesis of Alzheimer's disease or if they are biomarkers for systemic changes during preclinical phases of the disease.

15.
Sci Rep ; 11(1): 12695, 2021 06 16.
Artigo em Inglês | MEDLINE | ID: mdl-34135352

RESUMO

Caspase-6 (Casp6) is implicated in Alzheimer disease (AD) cognitive impairment and pathology. Hippocampal atrophy is associated with cognitive impairment in AD. Here, a rare functional exonic missense CASP6 single nucleotide polymorphism (SNP), causing the substitution of asparagine with threonine at amino acid 73 in Casp6 (Casp6N73T), was associated with hippocampal subfield CA1 volume preservation. Compared to wild type Casp6 (Casp6WT), recombinant Casp6N73T altered Casp6 proteolysis of natural substrates Lamin A/C and α-Tubulin, but did not alter cleavage of the Ac-VEID-AFC Casp6 peptide substrate. Casp6N73T-transfected HEK293T cells showed elevated Casp6 mRNA levels similar to Casp6WT-transfected cells, but, in contrast to Casp6WT, did not accumulate active Casp6 subunits nor show increased Casp6 enzymatic activity. Electrophysiological and morphological assessments showed that Casp6N73T recombinant protein caused less neurofunctional damage and neurodegeneration in hippocampal CA1 pyramidal neurons than Casp6WT. Lastly, CASP6 mRNA levels were increased in several AD brain regions confirming the implication of Casp6 in AD. These studies suggest that the rare Casp6N73T variant may protect against hippocampal atrophy due to its altered catalysis of natural protein substrates and intracellular instability thus leading to less Casp6-mediated damage to neuronal structure and function.


Assuntos
Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Região CA1 Hipocampal/patologia , Caspase 6/genética , Caspase 6/metabolismo , Polimorfismo de Nucleotídeo Único , Transmissão Sináptica , Doença de Alzheimer/enzimologia , Substituição de Aminoácidos , Encéfalo/enzimologia , Encéfalo/patologia , Caspase 1/genética , Caspase 1/metabolismo , Caspase 6/química , Precursores Enzimáticos/metabolismo , Células HEK293 , Hipocampo , Humanos , Lamina Tipo A/metabolismo , Mutação de Sentido Incorreto , Degeneração Neural , Células Piramidais/citologia , Células Piramidais/fisiologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Proteínas Recombinantes/metabolismo , Tubulina (Proteína)/metabolismo
16.
Brief Bioinform ; 22(6)2021 11 05.
Artigo em Inglês | MEDLINE | ID: mdl-33971669

RESUMO

A large number of genetic variations have been identified to be associated with Alzheimer's disease (AD) and related quantitative traits. However, majority of existing studies focused on single types of omics data, lacking the power of generating a community including multi-omic markers and their functional connections. Because of this, the immense value of multi-omics data on AD has attracted much attention. Leveraging genomic, transcriptomic and proteomic data, and their backbone network through functional relations, we proposed a modularity-constrained logistic regression model to mine the association between disease status and a group of functionally connected multi-omic features, i.e. single-nucleotide polymorphisms (SNPs), genes and proteins. This new model was applied to the real data collected from the frontal cortex tissue in the Religious Orders Study and Memory and Aging Project cohort. Compared with other state-of-art methods, it provided overall the best prediction performance during cross-validation. This new method helped identify a group of densely connected SNPs, genes and proteins predictive of AD status. These SNPs are mostly expression quantitative trait loci in the frontal region. Brain-wide gene expression profile of these genes and proteins were highly correlated with the brain activation map of 'vision', a brain function partly controlled by frontal cortex. These genes and proteins were also found to be associated with the amyloid deposition, cortical volume and average thickness of frontal regions. Taken together, these results suggested a potential pathway underlying the development of AD from SNPs to gene expression, protein expression and ultimately brain functional and structural changes.

17.
PLoS Med ; 18(5): e1003615, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-34043628

RESUMO

BACKGROUND: While Alzheimer disease (AD) and vascular dementia (VaD) may be accelerated by hypercholesterolemia, the mechanisms underlying this association are unclear. We tested whether dysregulation of cholesterol catabolism, through its conversion to primary bile acids (BAs), was associated with dementia pathogenesis. METHODS AND FINDINGS: We used a 3-step study design to examine the role of the primary BAs, cholic acid (CA), and chenodeoxycholic acid (CDCA) as well as their principal biosynthetic precursor, 7α-hydroxycholesterol (7α-OHC), in dementia. In Step 1, we tested whether serum markers of cholesterol catabolism were associated with brain amyloid accumulation, white matter lesions (WMLs), and brain atrophy. In Step 2, we tested whether exposure to bile acid sequestrants (BAS) was associated with risk of dementia. In Step 3, we examined plausible mechanisms underlying these findings by testing whether brain levels of primary BAs and gene expression of their principal receptors are altered in AD. Step 1: We assayed serum concentrations CA, CDCA, and 7α-OHC and used linear regression and mixed effects models to test their associations with brain amyloid accumulation (N = 141), WMLs, and brain atrophy (N = 134) in the Baltimore Longitudinal Study of Aging (BLSA). The BLSA is an ongoing, community-based cohort study that began in 1958. Participants in the BLSA neuroimaging sample were approximately 46% male with a mean age of 76 years; longitudinal analyses included an average of 2.5 follow-up magnetic resonance imaging (MRI) visits. We used the Alzheimer's Disease Neuroimaging Initiative (ADNI) (N = 1,666) to validate longitudinal neuroimaging results in BLSA. ADNI is an ongoing, community-based cohort study that began in 2003. Participants were approximately 55% male with a mean age of 74 years; longitudinal analyses included an average of 5.2 follow-up MRI visits. Lower serum concentrations of 7α-OHC, CA, and CDCA were associated with higher brain amyloid deposition (p = 0.041), faster WML accumulation (p = 0.050), and faster brain atrophy mainly (false discovery rate [FDR] p = <0.001-0.013) in males in BLSA. In ADNI, we found a modest sex-specific effect indicating that lower serum concentrations of CA and CDCA were associated with faster brain atrophy (FDR p = 0.049) in males.Step 2: In the Clinical Practice Research Datalink (CPRD) dataset, covering >4 million registrants from general practice clinics in the United Kingdom, we tested whether patients using BAS (BAS users; 3,208 with ≥2 prescriptions), which reduce circulating BAs and increase cholesterol catabolism, had altered dementia risk compared to those on non-statin lipid-modifying therapies (LMT users; 23,483 with ≥2 prescriptions). Patients in the study (BAS/LMT) were approximately 34%/38% male and with a mean age of 65/68 years; follow-up time was 4.7/5.7 years. We found that BAS use was not significantly associated with risk of all-cause dementia (hazard ratio (HR) = 1.03, 95% confidence interval (CI) = 0.72-1.46, p = 0.88) or its subtypes. We found a significant difference between the risk of VaD in males compared to females (p = 0.040) and a significant dose-response relationship between BAS use and risk of VaD (p-trend = 0.045) in males.Step 3: We assayed brain tissue concentrations of CA and CDCA comparing AD and control (CON) samples in the BLSA autopsy cohort (N = 29). Participants in the BLSA autopsy cohort (AD/CON) were approximately 50%/77% male with a mean age of 87/82 years. We analyzed single-cell RNA sequencing (scRNA-Seq) data to compare brain BA receptor gene expression between AD and CON samples from the Religious Orders Study and Memory and Aging Project (ROSMAP) cohort (N = 46). ROSMAP is an ongoing, community-based cohort study that began in 1994. Participants (AD/CON) were approximately 56%/36% male with a mean age of 85/85 years. In BLSA, we found that CA and CDCA were detectable in postmortem brain tissue samples and were marginally higher in AD samples compared to CON. In ROSMAP, we found sex-specific differences in altered neuronal gene expression of BA receptors in AD. Study limitations include the small sample sizes in the BLSA cohort and likely inaccuracies in the clinical diagnosis of dementia subtypes in primary care settings. CONCLUSIONS: We combined targeted metabolomics in serum and amyloid positron emission tomography (PET) and MRI of the brain with pharmacoepidemiologic analysis to implicate dysregulation of cholesterol catabolism in dementia pathogenesis. We observed that lower serum BA concentration mainly in males is associated with neuroimaging markers of dementia, and pharmacological lowering of BA levels may be associated with higher risk of VaD in males. We hypothesize that dysregulation of BA signaling pathways in the brain may represent a plausible biologic mechanism underlying these results. Together, our observations suggest a novel mechanism relating abnormalities in cholesterol catabolism to risk of dementia.


Assuntos
Ácidos e Sais Biliares/metabolismo , Demência/epidemiologia , Idoso , Idoso de 80 Anos ou mais , Ácidos e Sais Biliares/biossíntese , Demência/metabolismo , Feminino , Perfilação da Expressão Gênica , Humanos , Incidência , Masculino , Metabolômica , Pessoa de Meia-Idade , Farmacoepidemiologia , Reino Unido/epidemiologia
18.
J Alzheimers Dis ; 80(3): 1197-1207, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33646147

RESUMO

BACKGROUND: Whether the epidemiological association of amyloid-ß (Aß) and tau pathology in late-onset Alzheimer's disease (LOAD) is causal remains unclear. OBJECTIVE: We aimed to investigate the shared genetic background between the cerebrospinal fluid (CSF) biomarkers for Aß and tau pathology and the risk of LOAD. METHODS: We conducted a two-sample Mendelian randomization (MR) analysis. We used summary statistics of genome-wide association studies for CSF biomarkers (Aß1-42 [Aß], phosphorylated tau181 [p-tau], and total tau [t-tau]) in 3,146 individuals and for LOAD in 21,982 cases and 41,944 controls. We tested the association between changes in the genetically predicted CSF biomarkers and LOAD risk. RESULTS: We found a decrease in LOAD risk per one-standard-deviation (SD) increase in the genetically predicted CSF Aß (odds ratio [OR], 2.87×10-3 for AD; 95%confidence interval [CI], 1.54×10-4-0.05; p = 8.91×10-5). Conversely, we observed an increase in LOAD risk per one-SD increase in the genetically predicted CSF p-tau (OR, 19.46; 95%CI, 1.50-2.52×102; p = 0.02) and t-tau (OR, 33.80; 95%CI, 1.57-7.29×102; p = 0.02). However, only the association between p-tau and the risk for LOAD remained significant after the exclusion of the APOE variant (rs769449). CONCLUSION: We found the causal association between CSF biomarkers and the risk for LOAD. Our results suggest that the etiology of LOAD involves multiple biological processes, including the pathways of Aß and tau proteins. Further MR studies using large-scale data of multiple candidate biomarkers are needed to elucidate the pathophysiology of LOAD.


Assuntos
Doença de Alzheimer/líquido cefalorraquidiano , Doença de Alzheimer/genética , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Biomarcadores/líquido cefalorraquidiano , Proteínas tau/líquido cefalorraquidiano , Idoso , Idoso de 80 Anos ou mais , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Masculino , Análise da Randomização Mendeliana , Fatores de Risco
19.
NPJ Syst Biol Appl ; 7(1): 18, 2021 03 19.
Artigo em Inglês | MEDLINE | ID: mdl-33741983

RESUMO

Alzheimer's disease (AD) is a neurodegenerative disorder and is represented by complicated biological mechanisms and complexity of brain tissue. Our understanding of the complicated molecular architecture that contributes to AD progression benefits from performing comprehensive and systemic investigations with multi-layered molecular and biological data from different brain regions. Since recently different independent studies generated various omics data in different brain regions of AD patients, multi-omics data integration can be a useful resource for better comprehensive understanding of AD. Here we present a web platform, ADAS-viewer, that provides researchers with the ability to comprehensively investigate and visualize multi-omics data from multiple brain regions of AD patients. ADAS-viewer offers means to identify functional changes in transcript and exon expression (i.e., alternative splicing) along with associated genetic or epigenetic regulatory effects. Specifically, it integrates genomic, transcriptomic, methylation, and miRNA data collected from seven different brain regions (cerebellum, temporal cortex, dorsolateral prefrontal cortex, frontal pole, inferior frontal gyrus, parahippocampal gyrus, and superior temporal gyrus) across three independent cohort datasets. ADAS-viewer is particularly useful as a web-based application for analyzing and visualizing multi-omics data across multiple brain regions at both transcript and exon level, allowing the identification of candidate biomarkers of Alzheimer's disease.

20.
Neurobiol Aging ; 102: 200.e1-200.e11, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33640202

RESUMO

To identify genetic variants influencing cortical atrophy in Alzheimer's disease (AD), we performed genome-wide association studies (GWAS) of mean cortical thicknesses in 17 AD-related brain. In this study, we used neuroimaging and genetic data of 919 participants from the Alzheimer's Disease Neuroimaging Initiative cohort, which include 268 cognitively normal controls, 488 mild cognitive impairment, 163 AD individuals. We performed GWAS with 3,041,429 single nucleotide polymorphisms (SNPs) for cortical thickness. The results of GWAS indicated that rs10109716 in ST18 (ST18 C2H2C-type zinc finger transcription factor) and rs661526 in NFIA (nuclear factor I A) genes are significantly associated with mean cortical thicknesses of the left inferior frontal gyrus and left parahippocampal gyrus, respectively. The rs661526 regulates the expression levels of NFIA in the substantia nigra and frontal cortex and rs10109716 regulates the expression levels of ST18 in the thalamus. These results suggest a crucial role of identified genes for cortical atrophy and could provide further insights into the genetic basis of AD.

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