| 1. |
|
|
| 2. |
- Le Guen, Yann, et al.
(författare)
-
Multiancestry analysis of the HLA locus in Alzheimer's and Parkinson's diseases uncovers a shared adaptive immune response mediated by HLA-DRB1*04 subtypes.
- 2023
-
Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences (PNAS). - 1091-6490 .- 0027-8424. ; 120:36
-
Tidskriftsartikel (refereegranskat)abstract
- Across multiancestry groups, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson's disease (PD) and Alzheimer's disease (AD) versus controls. We demonstrate that the two diseases share the same protective association at the HLA locus. HLA-specific fine-mapping showed that hierarchical protective effects of HLA-DRB1*04 subtypes best accounted for the association, strongest with HLA-DRB1*04:04 and HLA-DRB1*04:07, and intermediary with HLA-DRB1*04:01 and HLA-DRB1*04:03. The same signal was associated with decreased neurofibrillary tangles in postmortem brains and was associated with reduced tau levels in cerebrospinal fluid and to a lower extent with increased Aβ42. Protective HLA-DRB1*04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, however only when acetylated at a lysine (K311), a common posttranslational modification central to tau aggregation. An HLA-DRB1*04-mediated adaptive immune response decreases PD and AD risks, potentially by acting against tau, offering the possibility of therapeutic avenues.
|
|
| 3. |
- Luo, Jiao, et al.
(författare)
-
Genetic Associations Between Modifiable Risk Factors and Alzheimer Disease
- 2023
-
Ingår i: JAMA Network Open. - : American Medical Association (AMA). - 2574-3805. ; 6:5
-
Tidskriftsartikel (refereegranskat)abstract
- IMPORTANCE An estimated 40% of dementia is potentially preventable by modifying 12 risk factors throughout the life course. However, robust evidence for most of these risk factors is lacking. Effective interventions should target risk factors in the causal pathway to dementia.OBJECTIVE To comprehensively disentangle potentially causal aspects of modifiable risk factors for Alzheimer disease (AD) to inspire new drug targeting and improved prevention.DESIGN, SETTING, AND PARTICIPANTS This genetic association study was conducted using 2-sample univariable and multivariable mendelian randomization. Independent genetic variants associated with modifiable risk factors were selected as instrumental variables from genomic consortia. Outcome data for AD were obtained from the European Alzheimer & Dementia Biobank (EADB), generated on August 31, 2021. Main analyses were conducted using the EADB clinically diagnosed end point data. All analyses were performed between April 12 and October 27, 2022.EXPOSURES Genetically determined modifiable risk factors. MAIN OUTCOMES AND MEASURES Odds ratios (ORs) and 95% CIs for AD were calculated per 1-unit change of genetically determined risk factors.RESULTS The EADB-diagnosed cohort included 39106 participants with clinically diagnosed AD and 401577 control participants without AD. The mean age ranged from 72 to 83 years for participants with AD and 51 to 80 years for control participants. Among participants with AD, 54% to 75% were female, and among control participants, 48% to 60% were female. Genetically determined high-density lipoprotein (HDL) cholesterol concentrations were associated with increased odds of AD (OR per 1-SD increase, 1.10 [95% CI, 1.05-1.16]). Genetically determined high systolic blood pressure was associated with increased risk of AD after adjusting for diastolic blood pressure (OR per 10-mm Hg increase, 1.22 [95% CI, 1.02-1.46]). In a second analysis to minimize bias due to sample overlap, the entire UK Biobank was excluded from the EADB consortium; odds for AD were similar for HDL cholesterol (OR per 1-SD unit increase, 1.08 [95% CI, 1.02-1.15]) and systolic blood pressure after adjusting for diastolic blood pressure (OR per 10-mm Hg increase, 1.23 [95% CI, 1.01-1.50]).CONCLUSIONS AND RELEVANCE This genetic association study found novel genetic associations between high HDL cholesterol concentrations and high systolic blood pressure with higher risk of AD. These findings may inspire new drug targeting and improved prevention implementation.
|
|
| 4. |
- Gueriau, Pierre, et al.
(författare)
-
A 365-Million-Year-Old Freshwater Community Reveals Morphological and Ecological Stasis in Branchiopod Crustaceans
- 2016
-
Ingår i: Current Biology. - : Elsevier BV. - 0960-9822 .- 1879-0445. ; 26:3, s. 383-390
-
Tidskriftsartikel (refereegranskat)abstract
- Branchiopod crustaceans are represented by fairy, tadpole, and clam shrimps (Anostraca, Notostraca, Laevicaudata, Spinicaudata), which typically inhabit temporary freshwater bodies, and water fleas (Cladoceromorpha), which live in all kinds of freshwater and occasionally marine environments [1, 2]. The earliest branchiopods occur in the Cambrian, where they are represented by complete body fossils from Sweden such as Rehbachiella kinnekullensis [3] and isolated mandibles preserved as small carbonaceous fossils [4-6] from Canada. The earliest known continental branchiopods are associated with hot spring environments [7] represented by the Early Devonian Rhynie Chert of Scotland (410 million years ago) and include possible stem-group or crown-group Anostraca, Notostraca, and clam shrimps or Cladoceromorpha [8-10], which differmorphologically fromtheirmodern counterparts [1, 2, 11]. Here we report the discovery of an ephemeral pool branchiopod community from the 365-million-year-old Strud locality of Belgium. It is characterized by new anostracans and spinicaudatans, closely resembling extant species, and the earliest notostracan, Strudops goldenbergi [12]. These branchiopods released resting eggs into the sediment in a manner similar to their modern representatives [1, 2]. We infer that this reproductive strategy was critical to overcoming environmental constraints such as seasonal desiccation imposed by living on land. The pioneer colonization of ephemeral freshwater pools by branchiopods in the Devonian was followed by remarkable ecological and morphological stasis that persists to the present day.
|
|
| 5. |
|
|
| 6. |
- Jansen, Iris E, et al.
(författare)
-
Genome-wide meta-analysis for Alzheimer's disease cerebrospinal fluid biomarkers.
- 2022
-
Ingår i: Acta neuropathologica. - : Springer Science and Business Media LLC. - 1432-0533 .- 0001-6322. ; 144:5, s. 821-842
-
Tidskriftsartikel (refereegranskat)abstract
- Amyloid-beta 42 (Aβ42) and phosphorylated tau (pTau) levels in cerebrospinal fluid (CSF) reflect core features of the pathogenesis of Alzheimer's disease (AD) more directly than clinical diagnosis. Initiated by the European Alzheimer & Dementia Biobank (EADB), the largest collaborative effort on genetics underlying CSF biomarkers was established, including 31 cohorts with a total of 13,116 individuals (discovery n = 8074; replication n = 5042 individuals). Besides the APOE locus, novel associations with two other well-established AD risk loci were observed; CR1 was shown a locus for Aβ42 and BIN1 for pTau. GMNC and C16orf95 were further identified as loci for pTau, of which the latter is novel. Clustering methods exploring the influence of all known AD risk loci on the CSF protein levels, revealed 4 biological categories suggesting multiple Aβ42 and pTau related biological pathways involved in the etiology of AD. In functional follow-up analyses, GMNC and C16orf95 both associated with lateral ventricular volume, implying an overlap in genetic etiology for tau levels and brain ventricular volume.
|
|
| 7. |
- Keller, Annika, et al.
(författare)
-
Mutations in the gene encoding PDGF-B cause brain calcifications in humans and mice
- 2013
-
Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 45:9, s. 1077-
-
Tidskriftsartikel (refereegranskat)abstract
- Calcifications in the basal ganglia are a common incidental finding and are sometimes inherited as an autosomal dominant trait ( idiopathic basal ganglia calcification (IBGC)). Recently, mutations in the PDGFRB gene coding for the platelet-derived growth factor receptor beta (PDGF-R beta) were linked to IBGC. Here we identify six families of different ancestry with nonsense and missense mutations in the gene encoding PDGF-B, the main ligand for PDGF-R beta. We also show that mice carrying hypomorphic Pdgfb alleles develop brain calcifications that show age-related expansion. The occurrence of these calcium depositions depends on the loss of endothelial PDGF-B and correlates with the degree of pericyte and blood-brain barrier deficiency. Thus, our data present a clear link between Pdgfb mutations and brain calcifications in mice, as well as between PDGFB mutations and IBGC in humans.
|
|
| 8. |
- Marquer, Laurent, et al.
(författare)
-
Pollen-based reconstruction of Holocene land-cover in mountain regions : Evaluation of the Landscape Reconstruction Algorithm in the Vicdessos valley, northern Pyrenees, France
- 2020
-
Ingår i: Quaternary Science Reviews. - : Elsevier. - 0277-3791 .- 1873-457X. ; 228, s. 1-15
-
Forskningsöversikt (refereegranskat)abstract
- Long-term perspectives on climate- and human-induced shifts in plant communities and tree line in mountains are often inferred from fossil pollen records. However, various factors, such as complex patterns of orographic wind fields and abundant insect-pollinated plants in higher altitudes, make pollen-based reconstruction in mountain regions difficult. Over the last decade the Landscape Reconstruction Algorithm (LRA) - a model-based approach in reconstruction of vegetation - has been successfully applied in various parts of the globe. However, evaluation of its effectiveness in mountain ranges is still limited. The present study assesses the extent to which the LRA approach helps quantify the local changes in vegetation cover at Vicdessos valley in northern French Pyrenees as a case study. In the study area well-dated sediment cores are available from eight bogs and ponds, 6-113 m in radius, located above the current tree line. We first use a simple simulation experiment to evaluate the way how pollen records from "landscape islands" (mountain tops and plateaus) would represent local vegetation and to clarify important factors affecting the LRA-based reconstruction in a mountainous region. This study then uses pollen records from these sites and vegetation and land-cover data both within a 50-km radius around the Vicdessos valley and within a 2-km radius from each site for evaluation of the REVEALS- and LOVE-based reconstruction of the regional and local plant cover, respectively, in the LRA approach. The land-cover data are complied for coniferous trees, broadleaved trees and non-forested areas from the CORINE and historical maps in three time windows: 1960-1970, 1990-2000 and 2000-2013. Major findings are as follows. (1) Accuracy of the regional vegetation estimates affects the reliability of the LRA-based reconstruction of vegetation within a 2-km radius; use of the CORINE data as input to the LOVE model improves reliability of the results over the use of the REVEALS-based estimates of regional vegetation. This implies that a systematic selection of pollen data only from sites above the tree line is problematic for estimating regional vegetation, and thus the entire LRA process. (2) Selection of the dispersal models for pollen transport (i.e. the Langrangian Stochastic Model vs. Gaussian Plume Model) does not affect significantly the LRA-based estimates at both the regional and local scales in the study area. (3) The LRA approach improves the pollen-based reconstruction of local vegetation compared to pollen percentage alone in northern Pyrenees. Although further empirical and simulation studies are necessary, our results emphasize the importance of site selection for the LRA-based reconstruction of vegetation in mountain regions. (C) 2019 Elsevier Ltd. All rights reserved.
|
|
| 9. |
|
|
| 10. |
- Miloudi, Khalil, et al.
(författare)
-
NOTCH1 signaling induces pathological vascular permeability in diabetic retinopathy
- 2019
-
Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : NATL ACAD SCIENCES. - 0027-8424 .- 1091-6490. ; 116:10, s. 4538-4547
-
Tidskriftsartikel (refereegranskat)abstract
- Diabetic macular edema is a major complication of diabetes resulting in loss of central vision. Although heightened vessel leakiness has been linked to glial and neuronal-derived factors, relatively little is known on the mechanisms by which mature endothelial cells exit from a quiescent state and compromise barrier function. Here we report that endothelial NOTCH1 signaling in mature diabetic retinas contributes to increased vascular permeability. By providing both human and mouse data, we show that NOTCH1 ligands JAGGED1 and DELTA LIKE-4 are up-regulated secondary to hyperglycemia and activate both canonical and rapid noncanonical NOTCH1 pathways that ultimately disrupt endothelial adherens junctions in diabetic retinas by causing dissociation of vascular endothelial-cadherin from beta-catenin. We further demonstrate that neutralization of NOTCH1 ligands prevents diabetes-induced retinal edema. Collectively, these results identify a fundamental process in diabetes-mediated vascular permeability and provide translational rational for targeting the NOTCH pathway (primarily JAGGED1) in conditions characterized by compromised vascular barrier function.
|
|
