Biology subjects

Baldeiras, I.

Publications and source records attributed to Baldeiras, I..

3 recordsLinked to original sources

bioRxiv2025

Transthyretin Levels and Instability in Alzheimer's Disease: Correlations with AD Biomarkers in a Cohort Study

BackgroundIn the last few decades, Transthyretin (TTR) has gained attention due to its implication in brain functions and neurodegenerative conditions, such as Alzheimers Disease (AD) by modulating amyloid-beta (A{beta}) pathology. This study aims to assess TTR levels and tetrameric instability in both plasma and cerebrospinal fluid (CSF) across the clinical continuum of AD, and to establish associations between TTR and key AD biomarkers, to enhance our understanding of the role of TTR in AD pathogenesis. MethodsWe conducted an evaluation of TTR levels and tetrameric instability in plasma and CSF in mild cognitive impairment (MCI-AD, n=29) and Dementia-AD (n=37) patients and examined the association with clinical, biochemical and genetic data. ResultsKey findings revealed a substantial decrease in plasma TTR levels in the Dementia-AD patients compared to the MCI-AD group, with a pronounced gender-specific effect identified in women, while no differences were detected in the CSF. The search for associations identified several correlations amongst MCI-AD patients where CSF TTR levels inversely correlated with markers of amyloid pathology and neurodegeneration such as A{beta}40 (r=-0.43, p < 0.02), p-Tau181 (r=-0.54, p < 0.03), t-Tau (r=-0.57, p< 0.001) and NfL (r=-0.49, p<0.006). CSF TTR instability also correlated negatively with CSF A{beta}42 (r=-0.6, p<0.001) and A{beta}42/A{beta}40 ratio (r=-0.58, p<0.001), indicating an association with increased amyloid burden. In the Dementia-AD group, plasma TTR levels correlated negatively with GFAP (r=-0.4, p<0.014), reflecting potential links with neuroinflammation. Additionally, plasma TTR instability correlated with CSF TTR instability (r=0.42, p < 0.009) and tau pathology markers (p-Tau181 (r=0.38, p < 0.02) and t-Tau (r=0.42, p<0.09)). Given the strong association between CSF TTR instability and A{beta}42, we investigated the effect of the peptide on TTR tetrameric instability and showed a clear increase in TTR instability in samples incubated with A{beta}42 for 24 hours (p<0.05). ConclusionsThis study emphasizes several associations between TTR and other key indicators of AD and suggests TTR is associated with A{beta} clearance, neurodegeneration, and neuroinflammation across different stages of the disease. We propose A{beta}42 and its increase in the brain as a factor destabilizing the TTR tetrameric fold, resulting in TTR impaired function.

neuroscience↗

bioRxiv2023

Unmasking Hidden Systemic Effects of Neurodegenerative Diseases: A Two-Pronged Approach to Biomarker Discovery

Identification of reliable blood biomarkers for neurodegenerative diseases (NDs) is crucial for translational and clinical research. However, conventional omics struggle with blood samples complexity, hindering desired outcomes. In this work the potential of High Molecular Weight (HMW) fractionation under non-denaturing conditions as a complementary approach to the conventional proteomics for identifying serum biomarkers in NDs was explored. A cohort of 58 serum samples of Alzheimers disease (AD), Parkinsons disease (PD) patients and control (CT) individuals was used to compare the two proteomics strategies: i) direct analysis of whole serum and ii) non-denaturing fractionation using 300 kDa cut-off filters (HMW serum). Although both approaches quantified a similar set of proteins, each approach captured a distinct subset of differentially altered proteins, suggesting that HMW fractionation identified additional types of alterations beyond conventional protein level changes. A discriminant model combining altered proteins from both datasets effectively distinguished between the three groups (AUC = 0.999 and median sensitivity and specificity of 97.4% and 91.7%, respectively). Importantly, this performance surpassed that of any model created using each method individually. Altogether, this work demonstrated that HMW fractionation can be a valuable complementary method to direct serum analysis and could enhance biomarker discovery. The 10 proteins included in the model (5 from each strategy), comprise clear evidence for the contribution of apolipoproteins for the diagnosis of NDs, revealing potential changes within lipid metabolism and the organization of macromolecules and their complexes, thereby uncovering effects that remain hidden from a conventional serum proteome analysis.

biochemistry↗

bioRxiv2022

Oxidative stress profiles of lymphoblasts from Amyotrophic Lateral Sclerosis patients with or without known SOD1 Mutations

Amyotrophic lateral sclerosis (ALS) is a fatal and rapidly progressing neurodegenerative disease that affects motor neurons. This disease is associated with oxidative stress especially in mutant superoxide dismutase 1 (mutSOD1) patients. However, less is known for the most prevalent sporadic ALS due to a lack of disease models. Here, we studied oxidative the stress profiles in lymphoblasts from ALS patients with mutSOD1 or unknown (undSOD1) mutations. mutSOD1 and undSOD1 lymphoblasts, as well as sex/age-matched controls (3/group) were obtained from Coriell and divided in 46 years-old-men (C1), 46 years-old-women (C2) or 26/27 years-old-men (C3) cohorts. Growth curves were performed, and several parameters associated with redox homeostasis were evaluated, including SOD activity and expression, general oxidative stress levels, lipid peroxidation, response to oxidative stimulus, glutathione redox cycle, catalase expression, and activity, and Nrf2 transcripts. Pooled (all cohorts) and paired (intra-cohort) statistical analyses were performed, followed by clustering and principal component analyses (PCA). Although a high heterogeneity among lymphoblast redox profiles was found between cohorts, clustering analysis based on 7 parameters with high chi-square ranking (total SOD activity, oxidative stress levels, catalase transcripts, SOD1 protein levels, metabolic response to mM concentrations of tert-butyl hydroperoxide, glutathione reductase activity, and Nrf2 transcript levels) provided a perfect separation between samples from healthy controls and ALS (undSOD1 and mutSOD1), also visualized in the PCA analysis. Our results show distinct redox signatures in lymphoblasts from mutSOD1, undSOD1, and healthy controls that can be used as therapeutic targets for ALS drug development. Highlights Lymphoblasts from ALS patients present altered redox properties Redox profiling evidenced total SOD and glutathione reductase activities, SOD1 protein levels, DCF fluorescence, catalase and Nrf2 transcripts, and tert-butyl hydroperoxide cytotoxicity, as discriminant features for experimental groups. Lymphoblast redox profiles may be helpful for patient stratification and precision medicine

cell biology↗