👤 Carla Roca

Alzheimer's disease (AD) is the leading cause of dementia, with an increasing incidence due to population aging. Approximately two-thirds of the people affected are women, possibly due to biological and hormonal factors. Also, lipids could play an important role in AD and show associations with cognitive impairment. Apolipoprotein E allele 4 (ApoE ε4) genotype and cardiovascular (CV) risk lipid ratios could be relevant in lipidomic studies. This work aims to identify specific alterations in plasma lipid profiles associated with AD in women and to explore these alterations related to ApoE and 2 CV risk lipid ratios. A lipidomic mass spectrometry-based method was applied to plasma samples from a clinical cohort of women. The patients were accurately classified into AD (n = 76) and non-AD (n = 74) groups by cerebrospinal fluid amyloid beta (Aβ)42/Aβ40 levels. The identified lipid species were evaluated and grouped into families and subfamilies. The lipids with significant differences between groups were examined in relation to ApoE genotype and 2 CV risk ratios (total cholesterol/high-density lipoprotein [HDL], triglycerides/HDL). Fatty acyls and monoacylglycerols showed higher levels in AD compared with non-AD, while diacylglycerols showed lower levels in AD. Also, specific subfamilies correlated with aging, CV risk, AD biomarkers, and cognitive status. Of the 627 lipid species detected, 45 showed statistically significant differences between groups, and some of them [lysophosphatidylcholine (24:1), diacylglycerol (18:0/18:1), and triacylglycerol (50:3)] showed significant associations with ApoE genotype and CV risk. This study identified associations between lipid profiles in women and AD pathology, ApoE ε4 genotype, and high CV risk ratios. Show less

FGFR1 genetic alterations are associated with brain malignancies, including FGFR1 mutations in familial and sporadic cases of low-grade glioneuronal tumors, suggesting intrinsic mechanisms of selective pressure toward FGFR1 multiple events arising in the context of a quiet genome. To decipher the molecular mechanisms triggered by multiple concurrent FGFR1 mutations, we have mapped the proximal interactome of wild-type, single- and double-mutant FGFR1 proteins through a BioID-MS approach. Our data reveal novel oncogenic functionality for the two hotspot mutations N546K and K656E, linked to evasion of lysosomal degradation. Further, we identified a modulatory tumor-suppressive role for the susceptibility variant R661P, which hampers the oncogenic potential of both hotspot N546K and K656E mutations by rescuing receptor degradation and reducing N546K affinity for the downstream effector PLCγ. Introducing the R661P missense variant was sufficient to abolish self-renewal capacity of oligodendroglioma cells and downregulate genes involved in neurodevelopment and neuro-glial cell fate decisions, both aspects overcome in the double mutants. This study sheds light on contextual oncogenic effects associated with FGFR1 alterations and their recurrence in low-mutation burden and therapy naive tumors. Show less

The growing prevalence of Alzheimer's disease calls for a drug that can simultaneously act towards several targets involved in the pathophysiology of the disease. In our study, we evaluated the potential of hydrazone and Show less

We studied the association of obesity-related single-nucleotide polymorphisms (OR-SNPs) with weight gain after antiretroviral therapy (ART) in people with human immunodeficiency virus (HIV; PWH). Participants were ART-naive PWH from the Spanish HIV Research Cohort who started ART from 2014 onward and had blood/DNA deposited in the cohort Biobank. The primary outcome was change in weight at 96 weeks after starting ART. We genotyped 14 OR-SNPs from a meta-analysis of genome-wide association studies of body mass index (BMI) loci. Changes over time in weight and BMI were studied using adjusted linear mixed models. A total of 1021 PWH were included. The mean weight gain over 96 weeks was 2.90 (95% confidence interval, 2.54-3.26) kg. Factors associated with higher weight gain were female sex, birth in sub-Saharan Africa, prior AIDS, CD4+ <200 cells/µL, HIV-RNA >100 000 copies/mL, negative hepatitis C virus serology, and use of tenofovir alafenamide. A significant association was found between ZC3H4 rs3810291 GG genotype and BCDIN3D/FAIM2 rs7138803 GG genotype polymorphisms and weight and BMI increase. The estimated adjusted mean (standard error [SE]) of weight gain was 4.26 (0.56) kg in ZC3H4 rs3810291 GG carriers and 2.66 (0.19) kg in AA/AG carriers (P = .007). Likewise the estimated weight gain at 96 weeks was 3.35 (0.29) kg in BCDIN3D/FAIM2 rs7138803 GG carriers and 2.51 (0.24) kg in AG/AA carriers (P = .020). Genetic factors may play a role in weight gain after ART initiation. Further work is needed to replicate our findings and understand how the identified SNPs lead to higher weight gain in this context. Show less