134 research outputs found
Tau Enhances α-Synuclein Aggregation and Toxicity in Cellular Models of Synucleinopathy
BACKGROUND: The simultaneous accumulation of different misfolded proteins in the central nervous system is a common feature in many neurodegenerative diseases. In most cases, co-occurrence of abnormal deposited proteins is observed in different brain regions and cell populations, but, in some instances, the proteins can be found in the same cellular aggregates. Co-occurrence of tau and α-synuclein (α-syn) aggregates has been described in neurodegenerative disorders with primary deposition of α-syn, such as Parkinson's disease and dementia with Lewy bodies. Although it is known that tau and α-syn have pathological synergistic effects on their mutual fibrillization, the underlying biological effects remain unclear. METHODOLOGY/PRINCIPAL FINDINGS: We used different cell models of synucleinopathy to investigate the effects of tau on α-syn aggregation. Using confocal microscopy and FRET-based techniques we observed that tau colocalized and interacted with α-syn aggregates. We also found that tau overexpression changed the pattern of α-syn aggregation, reducing the size and increasing the number of aggregates. This shift was accompanied by an increase in the levels of insoluble α-syn. Furthermore, co-transfection of tau increased secreted α-syn and cytotoxicity. CONCLUSIONS/SIGNIFICANCE: Our data suggest that tau enhances α-syn aggregation and toxicity and disrupts α-syn inclusion formation. This pathological synergistic effect between tau and α-syn may amplify the deleterious process and spread the damage in neurodegenerative diseases that show co-occurrence of both pathologies
Synaptic phosphorylated a-synuclein in dementia with Lewy bodies
Dementia with Lewy bodies is characterized by the accumulation of Lewy bodies and Lewy neurites in the CNS, both of which are
composed mainly of aggregated a-synuclein phosphorylated at Ser129. Although phosphorylated a-synuclein is believed to exert
toxic effects at the synapse in dementia with Lewy bodies and other a-synucleinopathies, direct evidence for the precise synaptic
localization has been difficult to achieve due to the lack of adequate optical microscopic resolution to study human synapses. In the
present study we applied array tomography, a microscopy technique that combines ultrathin sectioning of tissue with immunofluorescence
allowing precise identification of small structures, to quantitatively investigate the synaptic phosphorylated a-synuclein
pathology in dementia with Lewy bodies. We performed array tomography on human brain samples from five patients with
dementia with Lewy bodies, five patients with Alzheimer’s disease and five healthy control subjects to analyse the presence of
phosphorylated a-synuclein immunoreactivity at the synapse and their relationship with synapse size. Main analyses were performed
in blocks from cingulate cortex and confirmed in blocks from the striatum of cases with dementia with Lewy bodies. A
total of 1 318 700 single pre- or post-synaptic terminals were analysed. We found that phosphorylated a-synuclein is present
exclusively in dementia with Lewy bodies cases, where it can be identified in the form of Lewy bodies, Lewy neurites and
small aggregates (50.16 mm3). Between 19% and 25% of phosphorylated a-synuclein deposits were found in presynaptic terminals
mainly in the form of small aggregates. Synaptic terminals that co-localized with small aggregates of phosphorylated a-synuclein
were significantly larger than those that did not. Finally, a gradient of phosphorylated a-synuclein aggregation in synapses
(pre4pre + post4post-synaptic) was observed. These results indicate that phosphorylated a-synuclein is found at the presynaptic
terminals of dementia with Lewy bodies cases mainly in the form of small phosphorylated a-synuclein aggregates that are
associated with changes in synaptic morphology. Overall, our data support the notion that pathological phosphorylated a-synuclein
may disrupt the structure and function of the synapse in dementia with Lewy bodies.Peer ReviewedPostprint (author's final draft
Regional overlap of pathologies in Lewy body disorders
Q2Q1Artículo original216-224Paciente adultoLewy body disorders (LBD) are common neurodegenerative diseases characterized by the presence of aggregated a-synuclein in
Lewy bodies and Lewy neurites in the central and peripheral nervous
systems. The brains of patients with LBD often display other comorbid pathologies, i.e. insoluble tau, b-amyloid aggregates, TAR
DNA-binding protein 43 (TDP-43) deposits, and argyrophilic grain
disease (AGD). The incidence and physiological relevance of these
concurrent pathological findings remain controversial. We performed a semiquantitative detailed mapping of a-synuclein, tau, bamyloid (Ab), TDP-43, and AGD pathologies in 17 areas in 63 LBD
cases (44 with Parkinson disease [PD], 28 with dementia, and 19
with dementia with Lewy bodies). APOE and MAPT genetic variants
were also investigated. A majority of LBD cases had 2 or 3 concomitant findings, particularly Alzheimer disease-related pathology.
Pathological stages of tau, b-amyloid and a-synuclein pathologies
were increased in cases with dementia. Ab score was the best correlate of the time to dementia in PD. In addition, b-amyloid deposition
correlated with a-synuclein load in all groups. MAPT H1 haplotype did not influence any assessed pathology in PD. These results highlight the common concurrence of pathologies in patients with LBD
that may have an impact on the clinical expression of the diseases
Lack of evidence for a genetic association between FGF20 and Parkinson's disease in Finnish and Greek patients
BACKGROUND: Fibroblast growth factor 20 (FGF20) is a neurotrophic factor preferentially expressed in the substantia nigra of rat brain and could be involved in dopaminergic neurons survival. Recently, a strong genetic association has been found between FGF20 gene and the risk of suffering from Parkinson's disease (PD). Our aim was to replicate this association in two independent populations. METHODS: Allelic, genotypic, and haplotype frequencies of four biallelic polymorphisms were assessed in 151 sporadic PD cases and 186 controls from Greece, and 144 sporadic PD patients and 135 controls from Finland. RESULTS: No association was found in any of the populations studied. CONCLUSION: Taken together, these findings suggest that common genetic variants in FGF20 are not a risk factor for PD in, at least, some European populations
Genetic Associations Between Modifiable Risk Factors and Alzheimer Disease
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 39 106 participants with clinically diagnosed AD and 401 577 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
Leveraging large multi-center cohorts of Alzheimer disease endophenotypes to understand the role of Klotho heterozygosity on disease risk
Two genetic variants in strong linkage disequilibrium (rs9536314 and rs9527025) in the Klotho (KL) gene, encoding a transmembrane protein, implicated in longevity and associated with brain resilience during normal aging, were recently shown to be associated with Alzheimer disease (AD) risk in cognitively normal participants who are APOE ε4 carriers. Specifically, the participants heterozygous for this variant (KL-SVHET+) showed lower risk of developing AD. Furthermore, a neuroprotective effect of KL-VSHET+ has been suggested against amyloid burden for cognitively normal participants, potentially mediated via the regulation of redox pathways. However, inconsistent associations and a smaller sample size of existing studies pose significant hurdles in drawing definitive conclusions. Here, we performed a well-powered association analysis between KL-VSHET+ and five different AD endophenotypes; brain amyloidosis measured by positron emission tomography (PET) scans (n = 5,541) or cerebrospinal fluid Aβ42 levels (CSF; n = 5,093), as well as biomarkers associated with tau pathology: the CSF Tau (n = 5,127), phosphorylated Tau (pTau181; n = 4,778) and inflammation: CSF soluble triggering receptor expressed on myeloid cells 2 (sTREM2; n = 2,123) levels. Our results found nominally significant associations of KL-VSHET+ status with biomarkers for brain amyloidosis (e.g., CSF Aβ positivity; odds ratio [OR] = 0.67 [95% CI, 0.55–0.78], β = 0.72, p = 0.007) and tau pathology (e.g., biomarker positivity for CSF Tau; OR = 0.39 [95% CI, 0.19–0.77], β = -0.94, p = 0.007, and pTau; OR = 0.50 [95% CI, 0.27–0.96], β = -0.68, p = 0.04) in cognitively normal participants, 60–80 years old, who are APOE e4-carriers. Our work supports previous findings, suggesting that the KL-VSHET+ on an APOE ε4 genotype background may modulate Aβ and tau pathology, thereby lowering the intensity of neurodegeneration and incidence of cognitive decline in older controls susceptible to AD
The MS4A gene cluster is a key modulator of soluble TREM2 and Alzheimer's disease risk
Soluble triggering receptor expressed on myeloid cells 2 (sTREM2) in cerebrospinal fluid (CSF) has been associated with Alzheimer's disease (AD). TREM2 plays a critical role in microglial activation, survival, and phagocytosis;however, the pathophysiological role of sTREM2 in AD is not well understood. Understanding the role of sTREM2 in AD may reveal new pathological mechanisms and lead to the identification of therapeutic targets. We performed a genome-wide association study (GWAS) to identify genetic modifiers of CSF sTREM2 obtained from the Alzheimer's Disease Neuroimaging Initiative. Common variants in the membrane-spanning 4-domains subfamily A (MS4A) gene region were associated with CSF sTREM2 concentrations (rs1582763;P = 1.15 x 10(-15));this was replicated in independent datasets. The variants associated with increased CSF sTREM2 concentrations were associated with reduced AD risk and delayed age at onset of disease. The single-nucleotide polymorphism rs1582763 modified expression of the MS4A4A and MS4A6A genes in multiple tissues, suggesting that one or both of these genes are important for modulating sTREM2 production. Using human macrophages as a proxy for microglia, we found that MS4A4A and TREM2 colocalized on lipid rafts at the plasma membrane, that sTREM2 increased with MS4A4A overexpression, and that silencing of MS4A4A reduced sTREM2 production. These genetic, molecular, and cellular findings suggest that MS4A4A modulates sTREM2. These findings also provide a mechanistic explanation for the original GWAS signal in the MS4A locus for AD risk and indicate that TREM2 may be involved in AD pathogenesis not only in TREM2 risk-variant carriers but also in those with sporadic disease
Deleterious ABCA7 mutations and transcript rescue mechanisms in early onset Alzheimer’s disease
Multiancestry analysis of the HLA locus in Alzheimer's and Parkinson's diseases uncovers a shared adaptive immune response mediated by <i>HLA-DRB1*04</i> subtypes
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.</p
Investigating the genetic architecture of dementia with Lewy bodies: a two-stage genome-wide association study
Background Dementia with Lewy bodies is the second most common form of dementia in elderly people but has been overshadowed in the research field, partly because of similarities between dementia with Lewy bodies, Parkinson’s disease, and Alzheimer’s disease. So far, to our knowledge, no large-scale genetic study of dementia with Lewy bodies has been done. To better understand the genetic basis of dementia with Lewy bodies, we have done a genome-wide association study with the aim of identifying genetic risk factors for this disorder.
Methods In this two-stage genome-wide association study, we collected samples from white participants of European ancestry who had been diagnosed with dementia with Lewy bodies according to established clinical or pathological criteria. In the discovery stage (with the case cohort recruited from 22 centres in ten countries and the controls derived from two publicly available database of Genotypes and Phenotypes studies [phs000404.v1.p1 and phs000982.v1.p1] in the USA), we performed genotyping and exploited the recently established Haplotype Reference Consortium panel as the basis for imputation. Pathological samples were ascertained following autopsy in each individual brain bank, whereas clinical samples were collected by clinical teams after clinical examination. There was no specific timeframe for collection of samples. We did association analyses in all participants with dementia with Lewy bodies, and also in only participants with pathological diagnosis. In the replication stage, we performed genotyping of significant and suggestive results from the discovery stage. Lastly, we did a meta-analysis of both stages under a fixed-effects model and used logistic regression to test for association in each stage.
Findings This study included 1743 patients with dementia with Lewy bodies (1324 with pathological diagnosis) and 4454 controls (1216 patients with dementia with Lewy bodies vs 3791 controls in the discovery stage; 527 vs 663 in the replication stage). Results confirm previously reported associations: APOE (rs429358; odds ratio [OR] 2·40, 95% CI 2·14–2·70; p=1·05 × 10–⁴⁸), SNCA (rs7681440; OR 0·73, 0·66–0·81; p=6·39 × 10–¹⁰), and GBA (rs35749011; OR 2·55, 1·88–3·46; p=1·78 × 10–⁹). They also provide some evidence for a novel candidate locus, namely CNTN1 (rs7314908; OR 1·51, 1·27–1·79; p=2·21 × 10–⁶); further replication will be important. Additionally, we estimate the heritable component of dementia with Lewy bodies to be about 36%.
Interpretation Despite the small sample size for a genome-wide association study, and acknowledging the potential biases from ascertaining samples from multiple locations, we present the most comprehensive and well powered genetic study in dementia with Lewy bodies so far. These data show that common genetic variability has a role in the disease
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