| 1. |
- Jones, G., et al.
(författare)
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Genome-wide meta-analysis of muscle weakness identifies 15 susceptibility loci in older men and women
- 2021
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- Low muscle strength is an important heritable indicator of poor health linked to morbidity and mortality in older people. In a genome-wide association study meta-analysis of 256,523 Europeans aged 60 years and over from 22 cohorts we identify 15 loci associated with muscle weakness (European Working Group on Sarcopenia in Older People definition: n=48,596 cases, 18.9% of total), including 12 loci not implicated in previous analyses of continuous measures of grip strength. Loci include genes reportedly involved in autoimmune disease (HLA-DQA1p=4x10(-17)), arthritis (GDF5p=4x10(-13)), cell cycle control and cancer protection, regulation of transcription, and others involved in the development and maintenance of the musculoskeletal system. Using Mendelian randomization we report possible overlapping causal pathways, including diabetes susceptibility, haematological parameters, and the immune system. We conclude that muscle weakness in older adults has distinct mechanisms from continuous strength, including several pathways considered to be hallmarks of ageing. Muscle weakness has been associated with morbidity and mortality in older people. Here, the authors have investigated this trait further by performing a genome-wide meta-analysis of grip strength and Mendelian randomization to discover causal relationships between muscle weakness and other diseases.
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| 2. |
- Tijms, B. M., et al.
(författare)
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CSF Proteomic Alzheimer's Disease-Predictive Subtypes in Cognitively Intact Amyloid Negative Individuals
- 2021
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Ingår i: Proteomes. - : MDPI AG. - 2227-7382. ; 9:3
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Tidskriftsartikel (refereegranskat)abstract
- We recently discovered three distinct pathophysiological subtypes in Alzheimer's disease (AD) using cerebrospinal fluid (CSF) proteomics: one with neuronal hyperplasticity, a second with innate immune system activation, and a third subtype with blood-brain barrier dysfunction. It remains unclear whether AD proteomic subtype profiles are a consequence of amyloid aggregation, or might exist upstream from aggregated amyloid. We studied this question in 127 older individuals with intact cognition and normal AD biomarkers in two independent cohorts (EMIF-AD MBD and ADNI). We clustered 705 proteins measured in CSF that were previously related to AD. We identified in these cognitively intact individuals without AD pathology three subtypes: two subtypes were seen in both cohorts (n = 49 with neuronal hyperplasticity and n = 44 with blood-brain barrier dysfunction), and one only in ADNI (n = 12 with innate immune activation). The proteins specific for these subtypes strongly overlapped with AD subtype protein profiles (overlap coefficients 92%-71%). Longitudinal p(181)-tau and amyloid beta 1-42 (A beta 42) CSF analysis showed that in the hyperplasticity subtype p(181)-tau increased (beta = 2.6 pg/mL per year, p = 0.01) and A beta 42 decreased over time (beta = -4.4 pg/mL per year, p = 0.03), in the innate immune activation subtype p(181)-tau increased (beta = 3.1 pg/mL per year, p = 0.01) while in the blood-brain barrier dysfunction subtype A beta 42 decreased (beta = -3.7 pg/mL per year, p = 0.009). These findings suggest that AD proteomic subtypes might already manifest in cognitively normal individuals and may predispose for AD before amyloid has reached abnormal levels.
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| 3. |
- Tijms, B. M., et al.
(författare)
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Pathophysiological subtypes of Alzheimer's disease based on cerebrospinal fluid proteomics
- 2020
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Ingår i: Brain. - : Oxford University Press (OUP). - 0006-8950 .- 1460-2156. ; 143, s. 3776-3792
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Tidskriftsartikel (refereegranskat)abstract
- Alzheimer's disease is biologically heterogeneous, and detailed understanding of the processes involved in patients is critical for development of treatments. CSF contains hundreds of proteins, with concentrations reflecting ongoing (patho)physiological processes. This provides the opportunity to study many biological processes at the same time in patients. We studied whether Alzheimer's disease biological subtypes can be detected in CSF proteomics using the dual clustering technique non-negative matrix factorization. In two independent cohorts (EMIF-AD MBD and ADNI) we found that 705 (77% of 911 tested) proteins differed between Alzheimer's disease (defined as having abnormal amyloid, n=425) and controls (defined as having normal CSF amyloid and tau and normal cognition, n=127). Using these proteins for data-driven clustering, we identified three robust pathophysiological Alzheimer's disease subtypes within each cohort showing (i) hyperplasticity and increased BACE1 levels; (ii) innate immune activation; and (iii) blood-brain barrier dysfunction with low BACE1 levels. In both cohorts, the majority of individuals were labelled as having subtype 1 (80, 36% in EMIF-AD MBD; 117, 59% in ADNI), 71 (32%) in EMIF-AD MBD and 41 (21%) in ADNI were labelled as subtype 2, and 72 (32%) in EMIF-AD MBD and 39 (20%) individuals in ADNI were labelled as subtype 3. Genetic analyses showed that all subtypes had an excess of genetic risk for Alzheimer's disease (all P>0.01). Additional pathological comparisons that were available for a subset in ADNI suggested that subtypes showed similar severity of Alzheimer's disease pathology, and did not differ in the frequencies of co-pathologies, providing further support that found subtypes truly reflect Alzheimer's disease heterogeneity. Compared to controls, all non-demented Alzheimer's disease individuals had increased risk of showing clinical progression (all P<0.01). Compared to subtype 1, subtype 2 showed faster clinical progression after correcting for age, sex, level of education and tau levels (hazard ratio = 2.5; 95% confidence interval = 1.2, 5.1; P=0.01), and subtype 3 at trend level (hazard ratio = 2.1; 95% confidence interval = 1.0, 4.4; P=0.06). Together, these results demonstrate the value of CSF proteomics in studying the biological heterogeneity in Alzheimer's disease patients, and suggest that subtypes may require tailored therapy.
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| 4. |
- Tremel, Shirley, et al.
(författare)
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Structural basis for VPS34 kinase activation by Rab1 and Rab5 on membranes
- 2021
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- The lipid phosphatidylinositol-3-phosphate (PI3P) is a regulator of two fundamental but distinct cellular processes, endocytosis and autophagy, so its generation needs to be under precise temporal and spatial control. PI3P is generated by two complexes that both contain the lipid kinase VPS34: complex II on endosomes (VPS34/VPS15/Beclin 1/UVRAG), and complex I on autophagosomes (VPS34/VPS15/Beclin 1/ATG14L). The endosomal GTPase Rab5 binds complex II, but the mechanism of VPS34 activation by Rab5 has remained elusive, and no GTPase is known to bind complex I. Here we show that Rab5a-GTP recruits endocytic complex II to membranes and activates it by binding between the VPS34 C2 and VPS15 WD40 domains. Electron cryotomography of complex II on Rab5a-decorated vesicles shows that the VPS34 kinase domain is released from inhibition by VPS15 and hovers over the lipid bilayer, poised for catalysis. We also show that the GTPase Rab1a, which is known to be involved in autophagy, recruits and activates the autophagy-specific complex I, but not complex II. Both Rabs bind to the same VPS34 interface but in a manner unique for each. These findings reveal how VPS34 complexes are activated on membranes by specific Rab GTPases and how they are recruited to unique cellular locations. The phosphatidylinositol-3-phosphate (PI3P) is generated by the lipid kinase VPS34, in the context of VPS34 complex I on autophagosomes or complex II on endosomes. Biochemical and structural analyses provide insights into the mechanism of both VPS34 complexes recruitment to and activation on membranes by specific Rab GTPases.
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| 5. |
- Fjell, A. M., et al.
(författare)
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Self-reported Sleep Problems Related to Amyloid Deposition in Cortical Regions with High HOMER1 Gene Expression
- 2020
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Ingår i: Cerebral Cortex. - : Oxford University Press (OUP). - 1047-3211 .- 1460-2199. ; 30:4, s. 2144-2156
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Tidskriftsartikel (refereegranskat)abstract
- Sleep problems are related to the elevated levels of the Alzheimer's disease (AD) biomarker beta-amyloid (AD) Hypotheses about the causes of this relationship can be generated from molecular markers of sleep problems identified in rodents. A major marker of sleep deprivation is Homerla, a neural protein coded by the HOMER1 gene, which has also been implicated in brain A beta accumulation. Here, we tested whether the relationship between cortical A beta accumulation and self-reported sleep quality, as well as changes in sleep quality over 3 years, was stronger in cortical regions with high HOMER1 mRNA expression levels. In a sample of 154 cognitively healthy older adults, A beta correlated with poorer sleep quality cross-sectionally and longitudinally (n = 62), but more strongly in the younger than in older individuals. Effects were mainly found in regions with high expression of HOMER1. The anatomical distribution of the sleep-A beta relationship followed closely the A beta accumulation pattern in 69 patients with mild cognitive impairment or AD. Thus, the results indicate that the relationship between sleep problems and A beta accumulation may involve Homer1 activity in the cortical regions, where harbor A beta deposits in AD. The findings may advance our understanding of the relationship between sleep problems and AD risk.
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| 6. |
- Franke, A., et al.
(författare)
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Operationalizing Ocean Health : Toward Integrated Research on Ocean Health and Recovery to Achieve Ocean Sustainability
- 2020
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Ingår i: One Earth. - : Elsevier BV. - 2590-3330 .- 2590-3322. ; 2:6, s. 557-565
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Tidskriftsartikel (refereegranskat)abstract
- Protecting the ocean has become a major goal of international policy as human activities increasingly endanger the integrity of the ocean ecosystem, often summarized as “ocean health.” By and large, efforts to protect the ocean have failed because, among other things, (1) the underlying socio-ecological pathways have not been properly considered, and (2) the concept of ocean health has been ill defined. Collectively, this prevents an adequate societal response as to how ocean ecosystems and their vital functions for human societies can be protected and restored. We review the confusion surrounding the term “ocean health” and suggest an operational ocean-health framework in line with the concept of strong sustainability. Given the accelerating degeneration of marine ecosystems, the restoration of regional ocean health will be of increasing importance. Our advocated transdisciplinary and multi-actor framework can help to advance the implementation of more active measures to restore ocean health and safeguard human health and well-being.
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| 7. |
- Konijnenberg, E., et al.
(författare)
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APOE ϵ4 genotype-dependent cerebrospinal fluid proteomic signatures in Alzheimer's disease
- 2020
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Ingår i: Alzheimer's Research and Therapy. - : Springer Science and Business Media LLC. - 1758-9193. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Aggregation of amyloid β into plaques in the brain is one of the earliest pathological events in Alzheimer's disease (AD). The exact pathophysiology leading to dementia is still uncertain, but the apolipoprotein E (APOE) ϵ4 genotype plays a major role. We aimed to identify the molecular pathways associated with amyloid β aggregation using cerebrospinal fluid (CSF) proteomics and to study the potential modifying effects of APOE ϵ4 genotype. Methods: We tested 243 proteins and protein fragments in CSF comparing 193 subjects with AD across the cognitive spectrum (65% APOE ϵ4 carriers, average age 75 ± 7 years) against 60 controls with normal CSF amyloid β, normal cognition, and no APOE ϵ4 allele (average age 75 ± 6 years). Results: One hundred twenty-nine proteins (53%) were associated with aggregated amyloid β. APOE ϵ4 carriers with AD showed altered concentrations of proteins involved in the complement pathway and glycolysis when cognition was normal and lower concentrations of proteins involved in synapse structure and function when cognitive impairment was moderately severe. APOE ϵ4 non-carriers with AD showed lower expression of proteins involved in synapse structure and function when cognition was normal and lower concentrations of proteins that were associated with complement and other inflammatory processes when cognitive impairment was mild. Repeating analyses for 114 proteins that were available in an independent EMIF-AD MBD dataset (n = 275) showed that 80% of the proteins showed group differences in a similar direction, but overall, 28% effects reached statistical significance (ranging between 6 and 87% depending on the disease stage and genotype), suggesting variable reproducibility. Conclusions: These results imply that AD pathophysiology depends on APOE genotype and that treatment for AD may need to be tailored according to APOE genotype and severity of the cognitive impairment. © 2020 The Author(s).
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| 8. |
- Reus, L. M., et al.
(författare)
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Alzheimer's disease genetic risk variants show brain cell type-specific associations with protein levels in cerebrospinal fluid
- 2021
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Ingår i: Alzheimer's & dementia : the journal of the Alzheimer's Association. - : Wiley. - 1552-5279. ; 17
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Neuronal dysfunction is central to the clinical manifestation of Alzheimer's disease (AD). However, genome-wide studies also suggest important roles for non-neuronal brain cell-types such as microglia and astrocytes. Our objective was to study whether brain cell type-specific polygenic risk scores (PGRS) for AD, including single nucleotide polymorphisms (SNPs) of genes expressed in one brain cell type, showed relationships with levels of cerebrospinal fluid (CSF) AD markers in individuals across the clinical spectrum of AD. METHOD: We selected 1,535 subjects (552 controls/709 mild cognitive impairment/274 AD-dementia, age 71±8 years, 48%female) from the ADNI (N=617) and EMIF-AD MBD (N=918) study, who had genetic data available. We labelled AD risk genes as specific for neurons, astrocytes, microglia, oligodendrocytes or endothelial cells when more than 50% of the gene expression was produced by one cell type (otherwise as 'non-specific') according to the BRAIN RNASeq database (Zhang et al., 2014). We calculated cell type-specific-PGRS with cell type-corresponding SNPs (P<5e-8 ) using weights from De Rojas et al., (2020) AD case-control summary statistics. Associations between cell type-specific-PGRS and CSF biomarkers (amyloid-beta, total tau (t-tau), phosphorylated tau (p-tau), neurofilament light, neurogranin and YKL-40) were examined using linear regressions, adjusted for population structure, study, age and sex. RESULT: Of 40 AD risk genes, 26 had detectable RNA levels in at least one brain cell type. Of these, sixteen were cell type-specific: 11 were microglia-specific, 4 astrocyte-specific (including APOE) and 1 neuron-specific (Figure 1). Astrocyte-PGRS (P=1.4e-6 , Pwithout_APOE =.1) and microglia-PGRS (P=6.3e-3 ) were increased in AD-type dementia compared to controls, whereas other PGRS were not (Figure 2). Astrocyte-PGRS (including APOE) were most strongly associated with CSF amyloid-beta (P=1.4e-31 ), t-tau (P=6.3e-10 ), p-tau (P=4.9e-9 ), and neurogranin (P=0.01). Astrocyte-specific (excluding APOE) and microglia-specific PGRS-AD also associated with CSF amyloid-beta (P<0.05), and with p-tau at trend-level (Figure 2). Apart from the tentative association between neuron-PGRS and CSF YKL-40, no other associations were observed. CONCLUSION: Findings indicate that AD risk variants have cell type-specific associations with amyloid and tau pathology, which seems mostly expressed by astrocytes (also without APOE) and microglia, suggesting that these cell types play a role in amyloid pathogenesis. © 2021 the Alzheimer's Association.
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| 9. |
- Shi, Liu, et al.
(författare)
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Dickkopf-1 Overexpression in vitro Nominates Candidate Blood Biomarkers Relating to Alzheimer's Disease Pathology.
- 2020
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Ingår i: Journal of Alzheimer's disease : JAD. - : IOS Press. - 1875-8908 .- 1387-2877. ; 77:3, s. 1353-1368
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Tidskriftsartikel (refereegranskat)abstract
- Previous studies suggest that Dickkopf-1 (DKK1), an inhibitor of Wnt signaling, plays a role in amyloid-induced toxicity and hence Alzheimer's disease (AD). However, the effect of DKK1 expression on protein expression, and whether such proteins are altered in disease, is unknown.We aim to test whether DKK1 induced protein signature obtained in vitro were associated with markers of AD pathology as used in the amyloid/tau/neurodegeneration (ATN) framework as well as with clinical outcomes.We first overexpressed DKK1 in HEK293A cells and quantified 1,128 proteins in cell lysates using aptamer capture arrays (SomaScan) to obtain a protein signature induced by DKK1. We then used the same assay to measure the DKK1-signature proteins in human plasma in two large cohorts, EMIF (n = 785) and ANM (n = 677).We identified a 100-protein signature induced by DKK1 in vitro. Subsets of proteins, along with age and apolipoprotein E ɛ4 genotype distinguished amyloid pathology (A + T-N-, A+T+N-, A+T-N+, and A+T+N+) from no AD pathology (A-T-N-) with an area under the curve of 0.72, 0.81, 0.88, and 0.85, respectively. Furthermore, we found that some signature proteins (e.g., Complement C3 and albumin) were associated with cognitive score and AD diagnosis in both cohorts.Our results add further evidence for a role of DKK regulation of Wnt signaling in AD and suggest that DKK1 induced signature proteins obtained in vitro could reflect theATNframework as well as predict disease severity and progression in vivo.
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| 10. |
- Shi, L., et al.
(författare)
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Plasma Proteomic Biomarkers Relating to Alzheimer's Disease: A Meta-Analysis Based on Our Own Studies
- 2021
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Ingår i: Frontiers in Aging Neuroscience. - : Frontiers Media SA. - 1663-4365. ; 13
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Tidskriftsartikel (refereegranskat)abstract
- Background and Objective: Plasma biomarkers for the diagnosis and stratification of Alzheimer's disease (AD) are intensively sought. However, no plasma markers are well established so far for AD diagnosis. Our group has identified and validated various blood-based proteomic biomarkers relating to AD pathology in multiple cohorts. The study aims to conduct a meta-analysis based on our own studies to systematically assess the diagnostic performance of our previously identified blood biomarkers. Methods: To do this, we included seven studies that our group has conducted during the last decade. These studies used either Luminex xMAP or ELISA to measure proteomic biomarkers. As proteins measured in these studies differed, we selected protein based on the criteria that it must be measured in at least four studies. We then examined biomarker performance using random-effect meta-analyses based on the mean difference between biomarker concentrations in AD and controls (CTL), AD and mild cognitive impairment (MCI), MCI, and CTL as well as MCI converted to dementia (MCIc) and non-converted (MCInc) individuals. Results: An overall of 2,879 subjects were retrieved for meta-analysis including 1,053 CTL, 895 MCI, 882 AD, and 49 frontotemporal dementia (FTD) patients. Six proteins were measured in at least four studies and were chosen for meta-analyses for AD diagnosis. Of them, three proteins had significant difference between AD and controls, among which alpha-2-macroglobulin (A2M) and ficolin-2 (FCN2) increased in AD while fibrinogen gamma chain (FGG) decreased in AD compared to CTL. Furthermore, FGG significantly increased in FTD compared to AD. None of the proteins passed the significance between AD and MCI, or MCI and CTL, or MCIc and MCInc, although complement component 4 (CC4) tended to increase in MCIc individuals compared to MCInc. Conclusions: The results suggest that A2M, FCN2, and FGG are promising biomarkers to discriminate AD patients from controls, which are worthy of further validation.
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