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  • 1
    Online-Ressource
    Online-Ressource
    Protective association of HLA‐DRB1 *04 subtypes in neurodegenerative diseases implicates acetylated tau PHF6 sequences
    Wiley ; 2022
    In:  Alzheimer's & Dementia Vol. 18, No. S3 ( 2022-12)
    Details
    In: Alzheimer's & Dementia, Wiley, Vol. 18, No. S3 ( 2022-12)
    Kurzfassung: Alzheimer’s disease (AD), Parkinson’s disease (PD), Amyotrophic Lateral Sclerosis (ALS) and other neurodegenerative diseases are responsible for considerable morbidity and mortality. With incidence rising with aging, these also represent a growing societal challenge. Pathophysiology involves accumulation of tau (neurofibrillary tangles) and Amyloid‐β‐rich (amyloid plaques) aggregates in AD, α‐synuclein‐rich aggregates (Lewy bodies) in PD and TDP‐43 aggregates in ALS, although co‐presence of these aggregates may occur. Consensus is also growing that tau may also play a key role in PD and ALS. Method Using genome‐wide association data, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with PD or Alzheimer’s AD disease versus controls across ancestry groups. Result A shared genetic association was observed across diseases at rs601945 (PD: odds ratio (OR)=0.84; 95% confidence interval, [0.80; 0.88]; p=2.2x10 ‐13 ; AD: OR=0.91[0.89; 0.93]; p=1.8x10 ‐22 ), and with a protective HLA association recently reported in ALS. Hierarchical protective effects of HLA‐DRB1 *04 subtypes best accounted for the association, strongest with HLA‐DRB1 *04:04 and HLA‐DRB1 *04:07, intermediary with HLA‐DRB1 *04:01 and HLA‐DRB1 *04:03, and absent for HLA‐DRB1 *04:05. The same signal was associated with decreased neurofibrillary tangles (but not neuritic plaque density) in postmortem brains and was more strongly associated with tau levels than Aβ42 levels in the cerebrospinal fluid. Finally, protective HLA‐DRB1 *04 subtypes strongly bound the aggregation‐prone tau PHF6 sequence, but only when acetylated at K311, a modification central to aggregation. Conclusion An HLA‐DRB1 *04‐mediated adaptive immune response, potentially against tau, decreases PD, AD and ALS risk, offering the possibility of new therapeutic avenues.
    Materialart: Online-Ressource
    ISSN: 1552-5260 , 1552-5279
    URL: Issue
    URL: Article
    DOI: 10.1002/alz.v18.S3
    DOI: 10.1002/alz.060159
    Sprache: Englisch
    Verlag: Wiley
    Publikationsdatum: 2022
    ZDB Id: 2201940-6
    Standort Signatur Einschränkungen Verfügbarkeit
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    Online-Ressource
  • 2
    Online-Ressource
    Online-Ressource
    Assessment of genetic modulators in cerebrospinal fluid levels of YKL‐40, and C‐reactive protein: An association with Alzheimer disease
    Wiley ; 2021
    In:  Alzheimer's & Dementia Vol. 17, No. S5 ( 2021-12)
    Details
    In: Alzheimer's & Dementia, Wiley, Vol. 17, No. S5 ( 2021-12)
    Kurzfassung: Alzheimer's disease (AD) is one of the most complex progressive neurological diseases that cause memory loss and cognitive deterioration owing to the death of brain cells. Some potential biomarkers have been discovered in cerebrospinal fluid (CSF) which could help in the prediction of AD. These biomarkers are either associated with amyloid pathology or tau pathology. But some of the biomarkers are also associated with neuro‐Inflammation, which is the third potential event associated with AD pathogenesis[i]. The levels of YKL‐40 and C‐Reactive Protein(CRP) in CSF are the biomarkers, which are found to be associated with AD[ii] . In this study, we are investigating more about the roles of these biomarkers in AD pathogenesis. Method The analysis was performed on the DELCODE dataset (n=311). The findings were validated in ADNI(n=277) and requested the independent cohort ACE (n=543) to contribute to our study in meta‐analysis. The Z‐score is produced and utilized as a phenotype with sex, age, 3 Principal Component Analysis, and diagnosis as covariates in linear regression. Furtheron, we used DELCODE, ADNI, and ACE summary statistics to run random and fixed‐effect models for the meta‐analysis. Result Following the study, we discovered the genetic variants of YKL‐40, and CRP with genome‐wide significant P‐values (5 x 10 ‐8 ) and evidence of connection in all datasets. In these biomarkers, however, including diagnosis as a covariate plays important role. All of the biomarkers' lambda values indicate that there is no inflation in the analysis(λ = 1.0). There was no discernible difference in age or gender. According to the meta‐analysis the genome‐wide significant loci linked with YKL‐40 appear to be in the region of chr1 and chr3; and for CRP in chr6 and chr19. Conclusion Our findings imply that the important SNPs linked to these biomarkers are found in protein‐coding areas and are connected with inflammation. In the CSF of people with AD, levels of YKL40, and CRP are higher than in healthy people. Innate immune responses and neuro‐inflammatory signaling pathways are both affected by these proteins. Taken together, these findings emphasize the importance of comprehending the complexities of AD.
    Materialart: Online-Ressource
    ISSN: 1552-5260 , 1552-5279
    URL: Issue
    URL: Article
    DOI: 10.1002/alz.v17.S5
    DOI: 10.1002/alz.058575
    Sprache: Englisch
    Verlag: Wiley
    Publikationsdatum: 2021
    ZDB Id: 2201940-6
    Standort Signatur Einschränkungen Verfügbarkeit
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    Online-Ressource
  • 3
    Online-Ressource
    Online-Ressource
    Methylation age and inflammation in prodromal Alzheimer’s disease
    Wiley ; 2023
    In:  Alzheimer's & Dementia Vol. 19, No. S1 ( 2023-06)
    Details
    In: Alzheimer's & Dementia, Wiley, Vol. 19, No. S1 ( 2023-06)
    Kurzfassung: The most relevant risk factor in Alzheimer’s disease (AD) is age. Aging is a complex process involving several biological changes which lead to chronic cellular stress and to a sterile tissue inflammation. During aging cells become senescent which is seen as morphological changes and secretion of immune signaling mediators associated with systemic low‐grade inflammation. Interestingly, during neurodegenerative processes such AD, microglia, astrocytes, and vascular unit cells become senescent. To explore the potential connection between immune signaling mediators, ageing, and biomarkers of AD, we have quantified in CSF several immune related molecules link to AD and analyzed their connection with known biological clocks. Method Biological age was obtained by deriving the epigenetic clock in DNA derived from peripheral blood. To this end, DNA methylation data was generated using the EPIC array from Illumina in two cohorts including 348 individuals (cognitively normal, subjective cognitive decline and mild cognitive impairment) from DELCODE study and 267 individuals (mild cognitive impairment). Data was prepared and normalized using standard quality controls. Horvath’s and Hannum epiClocks were computed for all individuals in both cohorts. AD biomarkers including Amyloid‐ß, phosphor‐tau and total tau along with a panel of inflammation markers were measured in CSF samples. Result Both epiClocks showed a significant strong correlation with chronological age in both cohorts. Methylation age and chronological age showed both a significant association with classical AD biomarkers, as well as a subsets of inflammation markers. The meta‐analysis confirmed the association of the Epiclocks and the chronological age with all AD biomarkers as well as with YKL40, sTREM2, C‐1 and MIF. Based on the difference between the calculated epiClock and the chronological age, we derived an index reporting on increase in biological aging rate (age‐acceleration). This index, however, did not show significant association with any of the AD biomarkers and inflammation markers. Conclusion Our study shows a link between inflammatory markers and methylation age in both healthy aging and pre‐dementia stages of AD. However, biological clocks derived from peripheral tissue seem to be independent of potential AD pathology and inflammation occurring in the aging brain. Thus, these biomarkers are not increasing the odds for methylation age‐acceleration.
    Materialart: Online-Ressource
    ISSN: 1552-5260 , 1552-5279
    URL: Issue
    URL: Article
    DOI: 10.1002/alz.v19.S1
    DOI: 10.1002/alz.062706
    Sprache: Englisch
    Verlag: Wiley
    Publikationsdatum: 2023
    ZDB Id: 2201940-6
    Standort Signatur Einschränkungen Verfügbarkeit
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    Online-Ressource
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