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1.
bioRxiv ; 2024 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-38712030

RESUMO

Introduction: Alzheimer's disease (AD) is the most prevalent neurodegenerative disease, yet our comprehension predominantly relies on studies within the non-Hispanic White (NHW) population. Here we aimed to provide comprehensive insights into the proteomic landscape of AD across diverse racial and ethnic groups. Methods: Dorsolateral prefrontal cortex (DLPFC) and superior temporal gyrus (STG) brain tissues were donated from multiple centers (Mayo Clinic, Emory University, Rush University, Mt. Sinai School of Medicine) and were harmonized through neuropathological evaluation, specifically adhering to the Braak staging and CERAD criteria. Among 1105 DLPFC tissue samples (998 unique individuals), 333 were from African American donors, 223 from Latino Americans, 529 from NHW donors, and the rest were from a mixed or unknown racial background. Among 280 STG tissue samples (244 unique individuals), 86 were African American, 76 Latino American, 116 NHW and the rest were mixed or unknown ethnicity. All tissues were uniformly homogenized and analyzed by tandem mass tag mass spectrometry (TMT-MS). Results: As a Quality control (QC) measure, proteins with more than 50% missing values were removed and iterative principal component analysis was conducted to remove outliers within brain regions. After QC, 9,180 and 9,734 proteins remained in the DLPC and STG proteome, respectively, of which approximately 9,000 proteins were shared between regions. Protein levels of microtubule-associated protein tau (MAPT) and amyloid-precursor protein (APP) demonstrated AD-related elevations in DLPFC tissues with a strong association with CERAD and Braak across racial groups. APOE4 protein levels in brain were highly concordant with APOE genotype of the individuals. Discussion: This comprehensive region resolved large-scale proteomic dataset provides a resource for the understanding of ethnoracial-specific protein differences in AD brain.

2.
bioRxiv ; 2024 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-38659743

RESUMO

INTRODUCTION: Multi-omics studies in Alzheimer's disease (AD) revealed many potential disease pathways and therapeutic targets. Despite their promise of precision medicine, these studies lacked African Americans (AA) and Latin Americans (LA), who are disproportionately affected by AD. METHODS: To bridge this gap, Accelerating Medicines Partnership in AD (AMP-AD) expanded brain multi-omics profiling to multi-ethnic donors. RESULTS: We generated multi-omics data and curated and harmonized phenotypic data from AA (n=306), LA (n=326), or AA and LA (n=4) brain donors plus Non-Hispanic White (n=252) and other (n=20) ethnic groups, to establish a foundational dataset enriched for AA and LA participants. This study describes the data available to the research community, including transcriptome from three brain regions, whole genome sequence, and proteome measures. DISCUSSION: Inclusion of traditionally underrepresented groups in multi-omics studies is essential to discover the full spectrum of precision medicine targets that will be pertinent to all populations affected with AD.

3.
Parkinsonism Relat Disord ; 119: 105935, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38072719

RESUMO

INTRODUCTION: Substantial heterogeneity between individual patients in the clinical presentation of Parkinson's disease (PD) has led to the classification of distinct PD subtypes. However, genetic susceptibility factors for specific PD subtypes are not well understood. Therefore, the present study aimed to investigate the genetics of PD heterogeneity by performing a genome-wide association study (GWAS) of PD subtypes. METHODS: A total of 799 PD patients were included and classified into tremor-dominant (TD) (N = 345), akinetic-rigid (AR) (N = 227), gait-difficulty (GD) (N = 82), and mixed (MX) (N = 145) phenotypic subtypes. After array genotyping and subsequent imputation, a total of 7,918,344 variants were assessed for association with each PD subtype using logistic regression models that were adjusted for age, sex, and the top five principal components of GWAS data. RESULTS: We identified one genome-wide significant association (P < 5 × 10-8), which was between the MIR3976HG rs7504760 variant and the AR subtype (Odds ratio [OR] = 6.12, P = 2.57 × 10-8). Suggestive associations (P < 1 × 10-6) were observed regarding TD for RP11-497G19.3/RP11-497G19.1 rs7304254 (OR = 3.33, P = 3.89 × 10-7), regarding GD for HES2 rs111473931 (OR = 3.18, P = 6.85 × 10-7), RP11-400D2.3/CTD-2012I17.1 rs149082205 (OR = 8.96, P = 9.08 × 10-7), and RN7SL408P/SGK1 rs56161738 (OR = 2.97, P = 6.19 × 10-7), and regarding MX for MMRN2 rs112991171 (OR = 4.98, P = 1.02 × 10-7). CONCLUSION: Our findings indicate that genetic variation may account for part of the clinical heterogeneity of PD. In particular, we found a novel genome-wide significant association between MIR3976HG variation and the AR PD subtype. Replication of these findings will be important in order to better define the genetic architecture of clinical variability in PD disease presentation.


Assuntos
Doença de Parkinson , Humanos , Doença de Parkinson/genética , Doença de Parkinson/complicações , Estudo de Associação Genômica Ampla , Tremor/complicações , Razão de Chances
4.
Nat Commun ; 14(1): 6801, 2023 11 02.
Artigo em Inglês | MEDLINE | ID: mdl-37919278

RESUMO

Progressive supranuclear palsy (PSP) is a neurodegenerative parkinsonian disorder characterized by cell-type-specific tau lesions in neurons and glia. Prior work uncovered transcriptome changes in human PSP brains, although their cell-specificity is unknown. Further, systematic data integration and experimental validation platforms to prioritize brain transcriptional perturbations as therapeutic targets in PSP are currently lacking. In this study, we combine bulk tissue (n = 408) and single nucleus RNAseq (n = 34) data from PSP and control brains with transcriptome data from a mouse tauopathy and experimental validations in Drosophila tau models for systematic discovery of high-confidence expression changes in PSP with therapeutic potential. We discover, replicate, and annotate thousands of differentially expressed genes in PSP, many of which reside in glia-enriched co-expression modules and cells. We prioritize DDR2, STOM, and KANK2 as promising therapeutic targets in PSP with striking cross-species validations. We share our findings and data via our interactive application tool PSP RNAseq Atlas ( https://rtools.mayo.edu/PSP_RNAseq_Atlas/ ). Our findings reveal robust glial transcriptome changes in PSP, provide a cross-species systems biology approach, and a tool for therapeutic target discoveries in PSP with potential application in other neurodegenerative diseases.


Assuntos
Receptor com Domínio Discoidina 2 , Paralisia Supranuclear Progressiva , Tauopatias , Humanos , Animais , Camundongos , Paralisia Supranuclear Progressiva/patologia , Proteínas tau/metabolismo , Biologia de Sistemas , Tauopatias/patologia , Neuroglia/metabolismo
5.
Sci Rep ; 13(1): 16855, 2023 10 06.
Artigo em Inglês | MEDLINE | ID: mdl-37803069

RESUMO

Mounting evidence highlights the crucial role of aging in the pathogenesis of Alzheimer's disease (AD). We have previously explored human apoE-targeted replacement mice across different ages and identified distinct molecular pathways driven by aging. However, the specific contribution of different brain cell types to the gene modules underlying these pathways remained elusive. To bridge this knowledge gap, we employed a computational deconvolution approach to examine cell-type-specific gene expression profiles in major brain cell types, including astrocytes (AS), microglia (MG), oligodendroglia (OG), neurons (NEU), and vascular cells (VC). Our findings revealed that immune module genes were predominantly expressed in MG, OG, and VC. The lipid metabolism module genes were primarily expressed in AS, MG, and OG. The mitochondria module genes showed prominent expression in VC, and the synapse module genes were primarily expressed in NEU and VC. Furthermore, we identified intra- and inter-cell-type interactions among these module genes and validated their aging-associated expression changes using published single cell studies. Our study dissected bulk brain transcriptomics data at the cellular level, providing a closer examination of the cell-type contributions to the molecular pathways driven by aging.


Assuntos
Doença de Alzheimer , Transcriptoma , Camundongos , Humanos , Animais , Perfilação da Expressão Gênica , Doença de Alzheimer/metabolismo , Envelhecimento/genética , Encéfalo/metabolismo
6.
medRxiv ; 2023 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-37905059

RESUMO

The PINK1-PRKN pathway mediates a critical quality control to maintain mitochondrial health and function. Together the kinase-ligase pair identifies and decorate damaged mitochondria with phosphorylated ubiquitin (p-S65-Ub). This selective label serves as the mitophagy tag and facilitates their degradation via autophagy-lysosome system. While complete loss of PINK1 or PRKN function causes early-onset Parkinson disease, much broader mitophagy impairments are emerging across neurodegenerative disorders. We previously found age- and disease-dependent accumulation of p-S65-Ub signal in the hippocampus of autopsy brains with Lewy body disease (LBD). However, the contribution of genetic variation to mitochondrial damage and p-S65-Ub levels remains unknown in LBD cases. To identify novel regulators of PINK1-PRKN mitophagy in LBD, we performed an unbiased genome-wide association study of hippocampal p-S65-Ub level with 1,012 autopsy confirmed LBD samples. Using an established, mostly automated workflow, hippocampal sections were immunostained for p-S65-Ub, scanned, and quantified with unbiased algorithms. Functional validation of the significant hit was performed in animal model and human induced pluripotent stem cells (hiPSCs). We identified a strong association with p-S65-Ub for APOE4 (rs429358; ß : 0.50, 95% CI: 0.41 to 0.69; p =8.67x10 -25 ) and a genome-wide significant association for ZMIZ1 (rs6480922; ß : -0.33, 95% CI: -0.45 to -0.22; p =1.42x10 -8 ). The increased p-S65-Ub levels in APOE4 -carrier may be mediated by both co-pathology-dependent and -independent mechanisms, which was confirmed in Apoe-targeted replacement mice and hiPSC-derived astrocytes. Intriguingly, ZMIZ1 rs6480922 also significantly associated with increased brain weight and reduced neuropathological burden indicating a potential role as a resilience factor. Our findings nominate novel mitophagy regulators in LBD brain ( ZMIZ1 locus) and highlight a strong association of APOE4 with mitophagy alteration. With APOE4 being the strongest known risk factor for clinical Alzheimer's disease and dementia with Lewy bodies, our findings suggest a common mechanistic link underscoring the importance of mitochondrial quality control.

7.
Neurol Genet ; 9(5): e200086, 2023 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-37476022

RESUMO

Background and Objectives: Variants in the CWH43 gene have been associated with normal pressure hydrocephalus (NPH). We aimed to replicate these findings, identify additional CWH43 variants, and further define the clinical phenotype associated with CWH43 variants. Methods: We determined the prevalence of CWH43 variants by whole-genome sequencing (WGS) in 94 patients with NPH. The odds of having CWH43 variant carriers develop NPH were determined through comparison with 532 Mayo Clinic Biobank volunteers without a history of NPH. For patients with NPH, we documented the head circumference, prevalence of disproportionate enlargement of subarachnoid hydrocephalus (DESH), microvascular changes on MRI quantified by the Fazekas scale, and ambulatory response to ventriculoperitoneal shunting. Results: We identified rare (MAF <0.05) coding CWH43 variants in 15 patients with NPH. Ten patients (Leu533Terfs, n = 8; Lys696Asnfs, n = 2) harbored previously reported predicted loss-of-function variants, and combined burden analysis confirmed risk association with NPH (OR 2.60, 95% CI 1.12-6.03, p = 0.027). Additional missense variations observed included Ile292Thr (n = 2), Ala469Ser (n = 2), and Ala626Val (n = 1). Though not quite statistically significant, in single variable analysis, the odds of having a head circumference above the 75th percentile of normal controls was more than 5 times higher for CWH43 variant carriers compared with that for noncarriers (unadjusted OR 5.67, 95% CI 0.96-108.55, p = 0.057), and this was consistent after adjusting for sex and height (OR 5.42, 95% CI 0.87-106.37, p = 0.073). DESH was present in 56.7% of noncarriers and only 21.4% of carriers (p = 0.016), while sulcal trapping was also more prevalent among noncarriers (67.2% vs 35.7%, p = 0.030). All 8 of the 15 variant carriers who underwent ventriculoperitoneal shunting at our institution experienced ambulatory improvements. Discussion: CWH43 variants are frequent in patients with NPH. Predicted loss-of-function mutations were the most common; we identified missense mutations that require further study. Our findings suggest that congenital factors, rather than malabsorption or vascular dysfunction, are primary contributors to the CWH43-related NPH clinical syndrome.

8.
Mol Neurodegener ; 18(1): 2, 2023 01 07.
Artigo em Inglês | MEDLINE | ID: mdl-36609403

RESUMO

BACKGROUND: Alzheimer's disease (AD) is neuropathologically characterized by amyloid-beta (Aß) plaques and neurofibrillary tangles. The main protein components of these hallmarks include Aß40, Aß42, tau, phosphor-tau, and APOE. We hypothesize that genetic variants influence the levels and solubility of these AD-related proteins in the brain; identifying these may provide key insights into disease pathogenesis. METHODS: Genome-wide genotypes were collected from 441 AD cases, imputed to the haplotype reference consortium (HRC) panel, and filtered for quality and frequency. Temporal cortex levels of five AD-related proteins from three fractions, buffer-soluble (TBS), detergent-soluble (Triton-X = TX), and insoluble (Formic acid = FA), were available for these same individuals. Variants were tested for association with each quantitative biochemical measure using linear regression, and GSA-SNP2 was used to identify enriched Gene Ontology (GO) terms. Implicated variants and genes were further assessed for association with other relevant variables. RESULTS: We identified genome-wide significant associations at seven novel loci and the APOE locus. Genes and variants at these loci also associate with multiple AD-related measures, regulate gene expression, have cell-type specific enrichment, and roles in brain health and other neuropsychiatric diseases. Pathway analysis identified significant enrichment of shared and distinct biological pathways. CONCLUSIONS: Although all biochemical measures tested reflect proteins core to AD pathology, our results strongly suggest that each have unique genetic architecture and biological pathways that influence their specific biochemical states in the brain. Our novel approach of deep brain biochemical endophenotype GWAS has implications for pathophysiology of proteostasis in AD that can guide therapeutic discovery efforts focused on these proteins.


Assuntos
Doença de Alzheimer , Humanos , Doença de Alzheimer/metabolismo , Estudo de Associação Genômica Ampla , Peptídeos beta-Amiloides/metabolismo , Encéfalo/metabolismo , Placa Amiloide/patologia , Fenótipo , Apolipoproteínas E/metabolismo , Proteínas tau/metabolismo
9.
Front Genet ; 13: 984338, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36186441

RESUMO

The recent methodological advances in multi-omics approaches, including genomic, transcriptomic, metabolomic, lipidomic, and proteomic, have revolutionized the research field by generating "big data" which greatly enhanced our understanding of the molecular complexity of the brain and disease states. Network approaches have been routinely applied to single-omics data to provide critical insight into disease biology. Furthermore, multi-omics integration has emerged as both a vital need and a new direction to connect the different layers of information underlying disease mechanisms. In this review article, we summarize popular network analytic approaches for single-omics data and multi-omics integration and discuss how these approaches have been utilized in studying neurodegenerative diseases.

10.
J Exp Med ; 219(12)2022 12 05.
Artigo em Inglês | MEDLINE | ID: mdl-36107206

RESUMO

TREM2 is exclusively expressed by microglia in the brain and is strongly linked to the risk for Alzheimer's disease (AD). As microglial responses modulated by TREM2 are central to AD pathogenesis, enhancing TREM2 signaling has been explored as an AD therapeutic strategy. However, the effective therapeutic window targeting TREM2 is unclear. Here, by using microglia-specific inducible mouse models overexpressing human wild-type TREM2 (TREM2-WT) or R47H risk variant (TREM2-R47H), we show that TREM2-WT expression reduces amyloid deposition and neuritic dystrophy only during the early amyloid seeding stage, whereas TREM2-R47H exacerbates amyloid burden during the middle amyloid rapid growth stage. Single-cell RNA sequencing reveals suppressed disease-associated microglia (DAM) signature and reduced DAM population upon TREM2-WT expression in the early stage, whereas upregulated antigen presentation pathway is detected with TREM2-R47H expression in the middle stage. Together, our findings highlight the dynamic effects of TREM2 in modulating AD pathogenesis and emphasize the beneficial effect of enhancing TREM2 function in the early stage of AD development.


Assuntos
Doença de Alzheimer , Amiloidose , Doença de Alzheimer/patologia , Amiloide/metabolismo , Amiloidose/patologia , Animais , Encéfalo/patologia , Humanos , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Camundongos , Microglia/metabolismo , Receptores Imunológicos/genética , Receptores Imunológicos/metabolismo
11.
Nat Neurosci ; 25(8): 1020-1033, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35915180

RESUMO

The ε4 allele of the apolipoprotein E (APOE) gene, a genetic risk factor for Alzheimer's disease, is abundantly expressed in both the brain and periphery. Here, we present evidence that peripheral apoE isoforms, separated from those in the brain by the blood-brain barrier, differentially impact Alzheimer's disease pathogenesis and cognition. To evaluate the function of peripheral apoE, we developed conditional mouse models expressing human APOE3 or APOE4 in the liver with no detectable apoE in the brain. Liver-expressed apoE4 compromised synaptic plasticity and cognition by impairing cerebrovascular functions. Plasma proteome profiling revealed apoE isoform-dependent functional pathways highlighting cell adhesion, lipoprotein metabolism and complement activation. ApoE3 plasma from young mice improved cognition and reduced vessel-associated gliosis when transfused into aged mice, whereas apoE4 compromised the beneficial effects of young plasma. A human induced pluripotent stem cell-derived endothelial cell model recapitulated the plasma apoE isoform-specific effect on endothelial integrity, further supporting a vascular-related mechanism. Upon breeding with amyloid model mice, liver-expressed apoE4 exacerbated brain amyloid pathology, whereas apoE3 reduced it. Our findings demonstrate pathogenic effects of peripheral apoE4, providing a strong rationale for targeting peripheral apoE to treat Alzheimer's disease.


Assuntos
Doença de Alzheimer , Células-Tronco Pluripotentes Induzidas , Doença de Alzheimer/metabolismo , Animais , Apolipoproteína E3/genética , Apolipoproteína E3/metabolismo , Apolipoproteína E4/genética , Apolipoproteína E4/metabolismo , Apolipoproteínas E/genética , Encéfalo/metabolismo , Cognição , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Camundongos , Camundongos Transgênicos , Isoformas de Proteínas/metabolismo
12.
Alzheimers Res Ther ; 14(1): 104, 2022 07 27.
Artigo em Inglês | MEDLINE | ID: mdl-35897046

RESUMO

BACKGROUND: The S209F variant of Abelson Interactor Protein 3 (ABI3) increases risk for Alzheimer's disease (AD), but little is known about its function in relation to AD pathogenesis. METHODS: Here, we use a mouse model that is deficient in Abi3 locus to study how the loss of function of Abi3 impacts two cardinal neuropathological hallmarks of AD-amyloid ß plaques and tau pathology. Our study employs extensive neuropathological and transcriptomic characterization using transgenic mouse models and adeno-associated virus-mediated gene targeting strategies. RESULTS: Analysis of bulk RNAseq data confirmed age-progressive increase in Abi3 levels in rodent models of AD-type amyloidosis and upregulation in AD patients relative to healthy controls. Using RNAscope in situ hybridization, we localized the cellular distribution of Abi3 in mouse and human brains, finding that Abi3 is expressed in both microglial and non-microglial cells. Next, we evaluated Abi3-/- mice and document that both Abi3 and its overlapping gene, Gngt2, are disrupted in these mice. Using multiple transcriptomic datasets, we show that expression of Abi3 and Gngt2 are tightly correlated in rodent models of AD and human brains, suggesting a tight co-expression relationship. RNAseq of the Abi3-Gngt2-/- mice revealed upregulation of Trem2, Plcg2, and Tyrobp, concomitant with induction of an AD-associated neurodegenerative signature, even in the absence of AD-typical neuropathology. In APP mice, loss of Abi3-Gngt2 resulted in a gene dose- and age-dependent reduction in Aß deposition. Additionally, in Abi3-Gngt2-/- mice, expression of a pro-aggregant form of human tau exacerbated tauopathy and astrocytosis. Further, using in vitro culture assays, we show that the AD-associated S209F mutation alters the extent of ABI3 phosphorylation. CONCLUSIONS: These data provide an important experimental framework for understanding the role of Abi3-Gngt2 function and early inflammatory gliosis in AD. Our studies also demonstrate that inflammatory gliosis could have opposing effects on amyloid and tau pathology, highlighting the unpredictability of targeting immune pathways in AD.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal , Doença de Alzheimer , Amiloidose , Subunidades gama da Proteína de Ligação ao GTP , Animais , Humanos , Camundongos , Proteínas Adaptadoras de Transdução de Sinal/genética , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/genética , Amiloidose/genética , Encéfalo/metabolismo , Modelos Animais de Doenças , Gliose/metabolismo , Subunidades gama da Proteína de Ligação ao GTP/genética , Glicoproteínas de Membrana/metabolismo , Camundongos Transgênicos , Placa Amiloide/patologia , Receptores Imunológicos/metabolismo , Proteínas tau/genética , Proteínas tau/metabolismo
13.
Aging Cell ; 21(5): e13606, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35388616

RESUMO

Microglia have fundamental roles in health and disease; however, effects of age, sex, and genetic factors on human microglia have not been fully explored. We applied bulk and single-cell approaches to comprehensively characterize human microglia transcriptomes and their associations with age, sex, and APOE. We identified a novel microglial signature, characterized its expression in bulk tissue and single-cell microglia transcriptomes. We discovered microglial co-expression network modules associated with age, sex, and APOE-ε4 that are enriched for lipid and carbohydrate metabolism genes. Integrated analyses of modules with single-cell transcriptomes revealed significant overlap between age-associated module genes and both pro-inflammatory and disease-associated microglial clusters. These modules and clusters harbor known neurodegenerative disease genes including APOE, PLCG2, and BIN1. Meta-analyses with published bulk and single-cell microglial datasets further supported our findings. Thus, these data represent a well-characterized human microglial transcriptome resource and highlight age, sex, and APOE-related microglial immunometabolism perturbations with potential relevance in neurodegeneration.


Assuntos
Doença de Alzheimer , Doenças Neurodegenerativas , Doença de Alzheimer/metabolismo , Apolipoproteínas E/genética , Apolipoproteínas E/metabolismo , Humanos , Microglia/metabolismo , Doenças Neurodegenerativas/genética , Doenças Neurodegenerativas/metabolismo , Transcriptoma/genética
14.
Neurol Neurochir Pol ; 55(6): 559-566, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34642926

RESUMO

INTRODUCTION: Cognitive impairment is common in Parkinson's Disease, but the impact of predictive factors on incidence and rate of cognitive decline is incompletely understood. We aimed to determine the effects of sex and APOE allele status on cognitive performance in patients with Parkinson's Disease (PD). MATERIAL AND METHODS: We conducted a retrospective analysis of 325 clinically diagnosed PD patients who underwent one or more cognitive screenings with a Mini-Mental Status Examination (MMSE) or Mattis Dementia Rating Scale (DRS-2). We used proportional odds regression models to estimate odds ratios for higher versus lower cognitive scores in association with age, sex, education, disease duration, and APOE allele status. RESULTS: Higher cognitive scores were independently associated with female sex on the MMSE (OR 2.43; 95% CI 1.14, 5.14) and DRS-2 total (OR 4.14; 95% CI 2.01, 8.53). APOE ε4 dose was associated with lower DRS-2 totals (OR 0.42; 95% CI 0.22, 0.81), but there was no evidence of association with MMSE. Higher education level was also associated with higher scores on the MMSE (OR 1.22; 95% CI 1.07, 1.38) and DRS-2 total (OR 1.31; 95% CI 1.15, 1.50). Disease duration was not associated with cognitive performance on any measure when adjusting for age. CONCLUSION: Male sex and APOE ε4, along with age and lower education level, were associated with poorer cognitive performance among a population of predominantly non-demented PD patients.


Assuntos
Apolipoproteínas E , Disfunção Cognitiva , Doença de Parkinson , Fatores Sexuais , Apolipoproteínas E/genética , Disfunção Cognitiva/epidemiologia , Disfunção Cognitiva/genética , Feminino , Humanos , Masculino , Testes Neuropsicológicos , Doença de Parkinson/complicações , Doença de Parkinson/epidemiologia , Doença de Parkinson/genética , Estudos Retrospectivos
15.
Acta Neuropathol Commun ; 9(1): 93, 2021 05 21.
Artigo em Inglês | MEDLINE | ID: mdl-34020725

RESUMO

Cerebral amyloid angiopathy (CAA) contributes to accelerated cognitive decline in Alzheimer's disease (AD) dementia and is a common finding at autopsy. The APOEε4 allele and male sex have previously been reported to associate with increased CAA in AD. To inform biomarker and therapeutic target discovery, we aimed to identify additional genetic risk factors and biological pathways involved in this vascular component of AD etiology. We present a genome-wide association study of CAA pathology in AD cases and report sex- and APOE-stratified assessment of this phenotype. Genome-wide genotypes were collected from 853 neuropathology-confirmed AD cases scored for CAA across five brain regions, and imputed to the Haplotype Reference Consortium panel. Key variables and genome-wide genotypes were tested for association with CAA in all individuals and in sex and APOEε4 stratified subsets. Pathway enrichment was run for each of the genetic analyses. Implicated loci were further investigated for functional consequences using brain transcriptome data from 1,186 samples representing seven brain regions profiled as part of the AMP-AD consortium. We confirmed association of male sex, AD neuropathology and APOEε4 with increased CAA, and identified a novel locus, LINC-PINT, associated with lower CAA amongst APOEε4-negative individuals (rs10234094-C, beta = -3.70 [95% CI -0.49--0.24]; p = 1.63E-08). Transcriptome profiling revealed higher LINC-PINT expression levels in AD cases, and association of rs10234094-C with altered LINC-PINT splicing. Pathway analysis indicates variation in genes involved in neuronal health and function are linked to CAA in AD patients. Further studies in additional and diverse cohorts are needed to assess broader translation of our findings.


Assuntos
Doença de Alzheimer/genética , Apolipoproteína E4/genética , Angiopatia Amiloide Cerebral/genética , Variação Genética/genética , Estudo de Associação Genômica Ampla/métodos , Isoformas de Proteínas/genética , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/patologia , Angiopatia Amiloide Cerebral/patologia , Bases de Dados Genéticas , Feminino , Perfilação da Expressão Gênica/métodos , Humanos , Masculino , Pessoa de Meia-Idade
16.
Nat Commun ; 12(1): 2311, 2021 04 19.
Artigo em Inglês | MEDLINE | ID: mdl-33875655

RESUMO

Selective vulnerability of different brain regions is seen in many neurodegenerative disorders. The hippocampus and cortex are selectively vulnerable in Alzheimer's disease (AD), however the degree of involvement of the different brain regions differs among patients. We classified corticolimbic patterns of neurofibrillary tangles in postmortem tissue to capture extreme and representative phenotypes. We combined bulk RNA sequencing with digital pathology to examine hippocampal vulnerability in AD. We identified hippocampal gene expression changes associated with hippocampal vulnerability and used machine learning to identify genes that were associated with AD neuropathology, including SERPINA5, RYBP, SLC38A2, FEM1B, and PYDC1. Further histologic and biochemical analyses suggested SERPINA5 expression is associated with tau expression in the brain. Our study highlights the importance of embracing heterogeneity of the human brain in disease to identify disease-relevant gene expression.


Assuntos
Doença de Alzheimer/genética , Córtex Cerebral/metabolismo , Perfilação da Expressão Gênica/métodos , Hipocampo/metabolismo , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/diagnóstico , Autopsia , Córtex Cerebral/patologia , Feminino , Hipocampo/patologia , Humanos , Aprendizado de Máquina , Masculino , Emaranhados Neurofibrilares/genética , Emaranhados Neurofibrilares/metabolismo , Inibidor da Proteína C/genética , Inibidor da Proteína C/metabolismo , RNA-Seq/métodos , Proteínas tau/genética , Proteínas tau/metabolismo
17.
Brain Pathol ; 31(3): e12945, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33709463

RESUMO

TMEM106B has been recently implicated in multiple neurodegenerative diseases. Here, Rademakers et al. report a late-onset cerebellar Purkinje cell loss and progressive decline in motor function and gait deficits in a conventional Tmem106b-/- mouse model. By using high-power microscopy and bulk RNA sequencing, the authors further identify lysosomal and immune dysfunction as potential underlying mechanisms of the Purkinje cell loss.


Assuntos
Células de Purkinje , Animais , Modelos Animais de Doenças , Camundongos
19.
Mol Neurodegener ; 15(1): 38, 2020 07 13.
Artigo em Inglês | MEDLINE | ID: mdl-32660529

RESUMO

Large-scale brain bulk-RNAseq studies identified molecular pathways implicated in Alzheimer's disease (AD), however these findings can be confounded by cellular composition changes in bulk-tissue. To identify cell intrinsic gene expression alterations of individual cell types, we designed a bioinformatics pipeline and analyzed three AD and control bulk-RNAseq datasets of temporal and dorsolateral prefrontal cortex from 685 brain samples. We detected cell-proportion changes in AD brains that are robustly replicable across the three independently assessed cohorts. We applied three different algorithms including our in-house algorithm to identify cell intrinsic differentially expressed genes in individual cell types (CI-DEGs). We assessed the performance of all algorithms by comparison to single nucleus RNAseq data. We identified consensus CI-DEGs that are common to multiple brain regions. Despite significant overlap between consensus CI-DEGs and bulk-DEGs, many CI-DEGs were absent from bulk-DEGs. Consensus CI-DEGs and their enriched GO terms include genes and pathways previously implicated in AD or neurodegeneration, as well as novel ones. We demonstrated that the detection of CI-DEGs through computational deconvolution methods is promising and highlight remaining challenges. These findings provide novel insights into cell-intrinsic transcriptional changes of individual cell types in AD and may refine discovery and modeling of molecular targets that drive this complex disease.


Assuntos
Doença de Alzheimer/genética , Encéfalo/metabolismo , Regulação da Expressão Gênica/genética , Transcriptoma/genética , Biologia Computacional/métodos , Perfilação da Expressão Gênica/métodos , Humanos
20.
J Parasitol ; 105(4): 555-566, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31348717

RESUMO

Dispersal influences the evolution and adaptation of organisms, but it can be difficult to detect. Host-specific parasites provide information about the dispersal of their hosts and may be valuable for examining host dispersal that does not result in gene flow or that has low signals of gene flow. We examined the population connectivity of the buffy flower bat, Erophylla sezekorni (Chiroptera: Phyllostomidae), and its associated obligate ectoparasite, Trichobius frequens (Diptera: Streblidae), across a narrow oceanic channel in The Bahamas that has previously been implicated as a barrier to dispersal in bats. Due to the horizontal transmission of T. frequens, we were able to test the hypothesis that bats are dispersing across this channel, but this dispersal does not result in gene flow, occurs rarely, or started occurring recently. We developed novel microsatellite markers for the family Streblidae in combination with previously developed markers for bats to genotype individuals from 4 islands in The Bahamas. We provide evidence for a single population of the host, E. sezekorni, but 2 populations of its bat flies, potentially indicating a recent reduction of gene flow in E. sezekorni, rare dispersal, or infrequent transportation of bat flies with their hosts. Despite high population differentiation in bat flies indicated by microsatellites, mitochondrial DNA shows no polymorphism, suggesting that bacterial reproductive parasites may be contributing to mitochondrial DNA sweeps. Parasites, including bat flies, provide independent information about their hosts and can be used to test hypotheses of host dispersal that may be difficult to assess using host genetics alone.


Assuntos
Distribuição Animal/fisiologia , Quirópteros/fisiologia , Quirópteros/parasitologia , Dípteros/fisiologia , Ectoparasitoses/veterinária , Algoritmos , Alelos , Animais , Bahamas , Teorema de Bayes , Análise por Conglomerados , Sequência Consenso , DNA Mitocondrial/química , Dípteros/genética , Dípteros/microbiologia , Ectoparasitoses/parasitologia , Complexo IV da Cadeia de Transporte de Elétrons/química , Complexo IV da Cadeia de Transporte de Elétrons/genética , Interações Hospedeiro-Parasita , Cadeias de Markov , Alinhamento de Sequência/veterinária , Wolbachia/fisiologia
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