Biology subjects

Saavedra, J.

Publications and source records attributed to Saavedra, J..

4 recordsLinked to original sources

bioRxiv2025

Neuronal expression of S100B triggered by oligomeric Aβ peptide protects against cytoskeletal damage and synaptic loss

Alzheimers disease (AD) is a complex neurodegenerative disorder characterized by the intracellular deposition of Tau protein and extracellular deposition of amyloid-{beta} peptide (A{beta}). AD is also characterized by neuroinflammation and synapse loss, among others. The S100 family is a group of calcium-binding proteins with intra- and extracellular functions, that are important modulators of inflammatory responses. S100B, which is upregulated in AD patients and the most abundant member of this family, was shown to inhibit in vitro the aggregation and toxicity of A{beta}42, acting as a neuroprotective holdase-type chaperone. Although S100B is primarily produced by astrocytes, it is also expressed by various cells, including neurons. In this work, we investigated if S100B neuronal expression is triggered as a response to A{beta} toxic species, to provide protection during disease progression. We used the AD mouse model A{beta}PPswe/PS1A246E to show that neuronal S100B levels are significantly higher in 10-month-old animals, and cellular assays to demonstrate that A{beta} oligomers significantly increase S100B expression in SH-SY5Y cells, but not monomeric or fibrillar A{beta}. Using primary cultures of rat hippocampal neurons, we showed that S100B partially reverts A{beta}-induced cofilin-actin rods (synapse disruptors), and rescues the decrease in active synapses and post- (PSD-95) synaptic marker, imposed by A{beta} peptide. Altogether, these findings establish the neuroprotective activity of S100B in response to proteotoxic stress in cells, highlighting its chaperone function as a crucial factor in understanding proteostasis regulation in the diseased brain and identifying potential therapeutic targets.

neuroscience↗

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↗

bioRxiv2024

Inbreeding and gallbladder cancer risk: Homozygosity associations adjusted for indigenous American ancestry, BMI and genetic risk of gallstone disease

Latin Americans have a rich genetic make-up that translates into heterogeneous fractions of the autosomal genome in runs of homozygosity (FROH), and heterogeneous types and proportions of indigenous American ancestry. While autozygosity has been linked to several human diseases, very little is known about the relationship between inbreeding, genetic ancestry and cancer risk in Latin Americans. Chile has one of the highest incidences of gallbladder cancer (GBC) in the world, and here we investigated the association between inbreeding, GBC, gallstone disease (GSD) and body mass index (BMI) in 4029 genetically admixed Chileans. We calculated individual FROH above 1.5 Mb and weighted polygenic risk scores for GSD, and applied multiple logistic regression to assess the association between homozygosity and GBC risk. We found that homozygosity was due to a heterogeneous mixture of genetic drift and consanguinity in the study population. Although we found no association between homozygosity and overall GBC risk, we detected interactions between FROH and sex, age, and genetic risk of GSD on GBC risk. Specifically, the increase in GBC risk per 1% FROH was 19% in men (P-value = 0.002), 30% in those under 60 years of age (P-value = 0.001), and 12% in those with a genetic risk of GSD above the median (P-value = 0.01). The present study highlights the complex interplay between inbreeding, genetic ancestry and genetic risk of GSD in the development of GBC. The applied methodology and our findings underscore the importance of considering the population-specific genetic architecture, along with sex- and age specific-effects, when investigating the genetic basis of complex traits in Latin Americans.

genetics↗

bioRxiv2021

Neuroprotection in early stages of Alzheimers Disease is promoted by Transthyretin angiogenic properties

While still controversial, it has been demonstrated that vascular defects can precede the onset of the other AD hallmarks features, making it an important therapeutic target. Given that the protein transthyretin (TTR) has been established as neuroprotective in AD, here we investigated the influence of TTR in the vasculature. AD transgenic mice with TTR genetic reduction, AD/TTR+/-, exhibited a thicker BM in brain microvessels and decreased vessel length than animals with normal TTR levels, AD/TTR+/+. Further in vivo investigation, using the chick chorioallantoic membrane (CAM) assay, revealed that TTR is a pro-angiogenic molecule. Also, TTR increased the expression of key angiogenic molecules, by endothelial cells under tube formation conditions. We showed that TTR reduction leads to a thicker BM in AD mice than in NT animals, strengthening the idea that TTR is a neuroprotective protein. We also studied the effect of TTR tetrameric stabilization on BM thickness, showing that AD mice treated with iododiflunisal (IDIF) displayed a significant reduction of BM thickness and increased vessel length when compared to non-treated littermates. Our in vivo results show the involvement of TTR in angiogenesis, particularly as a modulator of vascular alterations occurring in AD. Since TTR is decreased early in AD, its tetrameric stabilization can represent a therapeutic avenue for the early treatment of AD through the maintenance of the vascular structure.

molecular biology↗