Increased levels of CSF total but not oligomeric or phosphorylated forms of alpha-synuclein in patients diagnosed with probable Alzheimer's disease.
Ontology highlight
ABSTRACT:
SUBMITTER: Majbour NK
PROVIDER: S-EPMC5223278 | biostudies-literature | 2017 Jan
REPOSITORIES: biostudies-literature
Publications
Increased levels of CSF total but not oligomeric or phosphorylated forms of alpha-synuclein in patients diagnosed with probable Alzheimer's disease.
Majbour Nour K NK Chiasserini Davide D Vaikath Nishant N NN Eusebi Paolo P Tokuda Takahiko T van de Berg Wilma W Parnetti Lucilla L Calabresi Paolo P El-Agnaf Omar M A OM
Scientific reports 20170110
Several studies reported an association between CSF alpha-synuclein (α-syn) and tau in Alzheimer's disease (AD), and demonstrated the significance of α-syn in improving the diagnostic sensitivity/specificity of classical AD CSF biomarkers. In the current study, we measured CSF levels of different α-syn species in a cohort of AD patients (n = 225) who showed a CSF profile typical of AD at baseline as well as in cognitively intact controls (n = 68). CSF total α-syn (t-α-syn) significantly increase ...[more]
Similar Datasets
Project description:BackgroundDespite decades of intensive research, to date, there is no accepted diagnosis for Parkinson's disease (PD) based on biochemical analysis of blood or CSF. However, neurodegeneration in the brains of PD patients begins several years before the manifestation of the clinical symptoms, pointing to serious flaw/limitations in this approach.ResultsTo explore the potential use of alpha-synuclein (?-syn) species as candidate biomarkers for PD, we generated specific antibodies directed against wide array of ?-syn species, namely total-, oligomeric- and phosphorylated-Ser129-?-syn (t-, o- and p-S129-?-syn). Next we sought to employ our antibodies to develop highly specific ELISA assays to quantify ?-syn species in biological samples. Finally we verified the usefulness of our assays in CSF samples from 46 PD patients and 48 age-matched healthy controls. We also assessed the discriminating power of combining multiple CSF ?-syn species with classical Alzheimer's disease biomarkers. The combination of CSF o-/t-?-syn, p-S129-?-syn and p-tau provided the best fitting predictive model for discriminating PD patients from controls. Moreover, CSF o-?-syn levels correlated significantly with the severity of PD motor symptoms (r?=?-0.37).ConclusionOur new ELISA assays can serve as research tools to address the unmet need for reliable CSF biomarkers for PD and related disorders.
| S-EPMC4717559 | biostudies-literature
Project description:The present study was to evaluate the diagnostic value of salivary total and oligomeric ?-synuclein levels in PD. Furthermore, we sought to explore the relationship between salivary total ?-synuclein and ?-synuclein SNP variants levels. 201 PD patients and 67 controls were recruited, of which there also had the genetic information of two positive ?-synuclein (SNCA) loci. Salivary total ?-synuclein was assayed using a highly sensitive Luminex assay and oligomeric ?-synuclein was quantified by the combination of Gel filtration chromatography and Western blot, respectively. From our analysis,No difference in salivary total ?-synuclein levels was found between PD patients and healthy controls, it decreased with age in PD patients, and was closely associated with genotypic distribution of rs11931074 and rs894278 in PD, respectively. After controlled for age and genders, G allele of rs11931074 was correlated with lower salivary total ?-synuclein levels, while G allele of rs894278 was also correlated with the higher levels. Simultaneously, the further study was shown that salivary oligomeric ?-synuclein in PD patients significantly increased comparing to healthy controls. In conclusions,our study firstly demonstrated that salivary total ?-synuclein levels could be manipulated by different ?-synuclein SNPs and salivary oligomeric ?-synuclein could be a potential diagnostic indicator of PD.
| S-EPMC4917865 | biostudies-literature
Project description:BACKGROUND:Asymptomatic carriers of leucine-rich repeat kinase 2 (LRRK2) gene mutations constitute an ideal population for discovering prodromal biomarkers of Parkinson's disease (PD). In this study, we aim to identify CSF candidate risk biomarkers of PD in individuals with LRRK2 mutation carriers. METHODS:We measured the levels of CSF total- (t-), oligomeric (o-) and phosphorylated S129 (pS129-) ?-syn, total-tau (tTau), phosphorylated threonine 181 tau (pTau), amyloid-beta 40 (A?-40), amyloid-beta-42 (A?-42) and 40 inflammatory chemokines in symptomatic (n?=?23) and asymptomatic (n?=?51) LRRK2 mutation carriers, subjects with a clinical diagnosis of PD (n?=?60) and age-matched healthy controls (n?=?34). General linear models corrected for age and gender were performed to assess differences in CSF biomarkers between the groups. Markers that varied significantly between the groups were then analyzed using backward-elimination logistic regression analysis to identify an ideal biomarkers panel of prodromal PD. RESULTS:Discriminant function analysis revealed low levels of CSF t-?-syn, high levels of CSF o-?-syn and TNF-? best discriminated asymptomatic LRRK2 mutation carriers from both symptomatic PD and healthy controls. Assessing the discriminative power using receiver operating curve analysis, an area under the curve >?0.80 was generated. CONCLUSIONS:The current study suggests that CSF t-, o-?-syn and TNF-? are candidate risk biomarkers for the detection of PD at the prodromal stage. Our findings also highlight the dynamic interrelationships between CSF proteins and the importance of using a biomarkers' panel approach for an accurate and timely diagnosis of PD.
| S-EPMC7201744 | biostudies-literature
Project description:In Parkinson's disease (PD), alpha-synuclein (a-syn) can be detected in biological fluids including saliva. Although previous studies found reduced a-syn total (a-syntotal) concentration in saliva of PD patients, no studies have previously examined salivary a-syn oligomers (a-synolig) concentrations or assessed the correlation between salivary a-syntotal, a-synolig and clinical features in a large cohort of PD patients. Is well known that a-synolig exerts a crucial neurotoxic effect in PD. We collected salivary samples from 60 PD patients and 40 age- and sex-comparable healthy subjects. PD was diagnosed according to the United Kingdom Brain Bank Criteria. Samples of saliva were analyzed by specific anti-a-syn and anti-oligomeric a-syn ELISA kits. A complete clinical evaluation of each patient was performed using MDS-Unified Parkinson's Disease Rating Scale, Beck Depression Inventory, Montreal Cognitive Assessment and Frontal Assessment Battery. Salivary a-syntotal was lower, whereas a-synolig was higher in PD patients than healthy subjects. The a-synolig/a-syntotal ratio was also higher in patients than in healthy subjects. Salivary a-syntotal concentration negatively correlated with that of a-synolig and correlated with several patients' clinical features. In PD, decreased salivary concentration of a-syntotal may reflect the reduction of a-syn monomers (a-synmon), as well as the formation of insoluble intracellular inclusions and soluble oligomers. The combined detection of a-syntotal and a-synolig in the saliva might help the early diagnosis of PD.
| S-EPMC4807094 | biostudies-literature
Project description:The intrinsically disordered human protein α-synuclein (αSN) can self-associate into oligomers and amyloid fibrils. Several lines of evidence suggest that oligomeric αSN is cytotoxic, making it important to devise strategies to either prevent oligomer formation and/or inhibit the ensuing toxicity. (-)-epigallocatechin gallate (EGCG) has emerged as a molecular modulator of αSN self-assembly, as it reduces the flexibility of the C-terminal region of αSN in the oligomer and inhibits the oligomer's ability to perturb phospholipid membranes and induce cell death. However, a detailed structural and kinetic characterization of this interaction is still lacking. Here, we use liquid-state NMR spectroscopy to investigate how EGCG interacts with monomeric and oligomeric forms of αSN. We find that EGCG can bind to all parts of monomeric αSN but exhibits highest affinity for the N-terminal region. Monomeric αSN binds ∼54 molecules of EGCG in total during oligomerization. Furthermore, kinetic data suggest that EGCG dimerization is coupled with the αSN association reaction. In contrast, preformed oligomers only bind ∼7 EGCG molecules per protomer, in agreement with the more compact nature of the oligomer compared with the natively unfolded monomer. In previously conducted cell assays, as little as 0.36 EGCG per αSN reduce oligomer toxicity by 50%. Our study thus demonstrates that αSN cytotoxicity can be inhibited by small molecules at concentrations at least an order of magnitude below full binding capacity. We speculate this is due to cooperative binding of protein-stabilized EGCG dimers, which in turn implies synergy between protein association and EGCG dimerization.
| S-EPMC8191297 | biostudies-literature
Project description:BackgroundRecently, several studies suggested potential involvements of α-synuclein in Alzheimer's disease (AD) pathophysiology. Higher concentrations of α-synuclein were reported in cerebrospinal fluid (CSF) of AD patients with a positive correlation towards CSF tau, indicating its possible role in AD. We analyzed the CSF biomarkers to verify whether α-synuclein could be an additional supported biomarker in AD diagnosis.MethodsIn this cross-sectional study, CSF samples of 71 early-onset AD, 34 late-onset AD, 11 mild cognitive impairment, 17 subjective cognitive decline, 45 Parkinson's disease, and 32 healthy control (HC) were collected. CSF amyloid-β1-42 (A), total tau (N), and phosphorylated tau181 (T) were measured by commercial ELISA kits, and in-house ELISA kit was developed to quantify α-synuclein. The cognitive assessments and amyloid-PET imaging were also performed.ResultsCSF α-synuclein manifested a tendency to increase in AD and to decreased in Parkinson's disease compared to HC. The equilibrium states of total tau and α-synuclein concentrations were changed significantly in AD, and the ratio of total tau/α-synuclein (N/αS) was dramatically increased in AD than HC. Remarkably, N/αS revealed a strong positive correlation with tau phosphorylation rate. Also, the combination of N/αS with amyloid-β1-42/phosphorylated tau181 ratio had the best diagnosis performance (AUC = 0.956, sensitivity = 96%, specificity = 87%). In concordance analysis, N/αS showed the higher diagnostic agreement with amyloid-β1-42 and amyloid-PET. Analysis of biomarker profiling with N/αS had distinctive characteristics and clustering of each group. Especially, among the group of suspected non-Alzheimer's disease pathophysiology, all A-T+N+ patients with N/αS+ were reintegrated into AD.ConclusionsThe high correlation of α-synuclein with tau and the elevated N/αS in AD supported the involvement of α-synuclein in AD pathophysiology. Importantly, N/αS improved the diagnostic performance, confirming the needs of incorporating α-synuclein as a biomarker for neurodegenerative disorders. The incorporation of a biomarker group [N/αS] could contribute to provide better understanding and diagnosis of neurodegenerative disorders.
| S-EPMC7359621 | biostudies-literature
Project description:Aggregation of ?-synuclein (?Syn) in neurons produces the hallmark cytopathology of Parkinson disease and related synucleinopathies. Since its discovery, ?Syn has been thought to exist normally in cells as an unfolded monomer. We recently reported that ?Syn can instead exist in cells as a helically folded tetramer that resists aggregation and binds lipid vesicles more avidly than unfolded recombinant monomers (Bartels, T., Choi, J. G., and Selkoe, D. J. (2011) Nature 477, 107-110). However, a subsequent study again concluded that cellular ?Syn is an unfolded monomer (Fauvet, B., Mbefo, M. K., Fares, M. B., Desobry, C., Michael, S., Ardah, M. T., Tsika, E., Coune, P., Prudent, M., Lion, N., Eliezer, D., Moore, D. J., Schneider, B., Aebischer, P., El-Agnaf, O. M., Masliah, E., and Lashuel, H. A. (2012) J. Biol. Chem. 287, 15345-15364). Here we describe a simple in vivo cross-linking method that reveals a major ~60-kDa form of endogenous ?Syn (monomer, 14.5 kDa) in intact cells and smaller amounts of ~80- and ~100-kDa forms with the same isoelectric point as the 60-kDa species. Controls indicate that the apparent 60-kDa tetramer exists normally and does not arise from pathological aggregation. The pattern of a major 60-kDa and minor 80- and 100-kDa species plus variable amounts of free monomers occurs endogenously in primary neurons and erythroid cells as well as neuroblastoma cells overexpressing ?Syn. A similar pattern occurs for the homologue, ?-synuclein, which does not undergo pathogenic aggregation. Cell lysis destabilizes the apparent 60-kDa tetramer, leaving mostly free monomers and some 80-kDa oligomer. However, lysis at high protein concentrations allows partial recovery of the 60-kDa tetramer. Together with our prior findings, these data suggest that endogenous ?Syn exists principally as a 60-kDa tetramer in living cells but is lysis-sensitive, making the study of natural ?Syn challenging outside of intact cells.
| S-EPMC3585072 | biostudies-literature
Project description:Alzheimer's disease (AD) and Lewy body diseases (LBD), e.g., Parkinson's disease (PD) dementia and dementia with Lewy bodies (DLB), are common causes of geriatric cognitive impairments. In addition, AD and LBD are often found in the same patients at autopsy; therefore, biomarkers that can detect the presence of both pathologies in living subjects are needed. In this investigation, we report the assessment of ?-synuclein (?-syn) in cerebrospinal fluid (CSF) and its association with CSF total tau (t-tau), phosphorylated tau181 (p-tau181), and amyloid beta1-42 (A?1-42) in subjects of the Alzheimer's Disease Neuroimaging Initiative (ADNI; n = 389), with longitudinal clinical assessments. A strong correlation was noted between ?-syn and t-tau in controls, as well as in patients with AD and mild cognitive impairment (MCI). However, the correlation is not specific to subjects in the ADNI cohort, as it was also seen in PD patients and controls enrolled in the Parkinson's Progression Markers Initiative (PPMI; n = 102). A bimodal distribution of CSF ?-syn levels was observed in the ADNI cohort, with high levels of ?-syn in the subjects with abnormally increased t-tau values. Although a correlation was also noted between ?-syn and p-tau181, there was a mismatch (?-syn-p-tau181-Mis), i.e., higher p-tau181 levels accompanied by lower ?-syn levels in a subset of ADNI patients. We hypothesize that this ?-syn-p-tau181-Mis is a CSF signature of concomitant LBD pathology in AD patients. Hence, we suggest that inclusion of measures of CSF ?-syn and calculation of ?-syn-p-tau181-Mis improves the diagnostic sensitivity/specificity of classic CSF AD biomarkers and better predicts longitudinal cognitive changes.
| S-EPMC3812407 | biostudies-literature
Project description:Alzheimer's disease (AD) features a dynamic sequence of amyloid deposition, neurodegeneration, and cognitive impairment. A significant fraction of AD brains also displays Lewy body pathology, suggesting that addition of classically Parkinson's disease-related proteins to the AD biomarker panel may be of value. To determine whether addition of cerebrospinal fluid (CSF) total ?-synuclein and its form phosphorylated at S129 (pS129) to the AD biomarker panel [Amyloid-?1-42 (A?42), tau, and phosphorylated tau (p-tau181)] improves its performance, we examined CSF samples collected longitudinally up to 7 years as part of the Alzheimer's Disease Neuroimaging Initiative. From 87 AD, 177 mild cognitive impairment (MCI), and 104 age-matched healthy controls, 792 baseline and longitudinal CSF samples were tested for total ?-synuclein, pS129, A?42, tau, and p-tau181. pS129, but not total ?-synuclein, was weakly associated with diagnosis at baseline when t-tau/A?42 was included in the statistical model (?=?0.0026, p?=?0.041, 95% CI [(0.0001)-(0.005)]). CSF ?-synuclein predicted Alzheimer's Disease Assessment Scale-Cognitive (?=?-0.59, p?=?0.0015, 95% CI [(-0.96)-(-0.23)]), memory (?=?0.4, p?=?0.00025, 95% CI [(0.16)-(0.59)]), and executive (0.62,<0.0001, 95% CI [(0.31)-(0.93)]) function composite scores, and progression from MCI to AD (?=?0.019, p?=?0.0011, 95% CI [(0.002)-(0.20)]). pS129 was associated with executive function (?=?-2.55, p?=?0.0085, 95% CI [(-4.45)-(-0.66)]). Lower values in the mismatch between ?-synuclein and p-tau181 predicted faster cognitive decline (?=?0.64, p?=?0.0012, 95% CI [(0.48)-(0.84)]). Longitudinal biomarker changes did not differ between groups, and may not reflect AD progression. The ?-synuclein-p-tau181-Mismatch could better predict longitudinal cognitive changes than classical AD markers alone, and its pathological correlates should be investigated further.
| S-EPMC5828159 | biostudies-literature
Project description:Despite clinical evidence indicating a close relationship between olfactory dysfunction and Alzheimer's disease (AD), further investigations are warranted to determine the diagnostic potential of nasal surrogate biomarkers for AD. In this study, we first identified soluble amyloid-? (A?), the key biomarker of AD, in patient nasal discharge using proteomic analysis. Then, we profiled the significant differences in A? oligomers level between patient groups with mild or moderate cognitive decline (n?=?39) and an age-matched normal control group (n?=?21) by immunoblot analysis and comparing the levels of A? by a self-standard method with interdigitated microelectrode sensor systems. All subjects received the Mini-Mental State Examination (MMSE), Clinical Dementia Rating (CDR), and the Global Deterioration Scale (GDS) for grouping. We observed higher levels of A? oligomers in probable AD subjects with lower MMSE, higher CDR, and higher GDS compared to the normal control group. Moreover, mild and moderate subject groups could be distinguished based on the increased composition of two oligomers, 12-mer A?*56 and 15-mer A?O, respectively. The longitudinal cohort study confirmed that the cognitive decline of mild AD patients with high nasal discharge A?*56 levels advanced to the moderate stage within three years. Our clinical evidence strongly supports the view that the presence of oligomeric A? proteins in nasal discharge is a potential surrogate biomarker of AD and an indicator of cognitive decline progression.
| S-EPMC7343787 | biostudies-literature