Biology subjects

Bernal, R.

Publications and source records attributed to Bernal, R..

5 recordsLinked to original sources

bioRxiv2025

Early Metabolic Alterations in Cerebrospinal Fluid Fatty Acid Profiles Linked to Cognitive Decline and All-Cause Dementia

BackgroundWhile All-cause dementia (ACD) may often be characterized by the abnormal deposition of extracellular {beta}-amyloid (A{beta}) in the brain cortex and hyperphosphorylated tau (p-tau) as neurofibrillary tangles intracellularly, there is a need to identify early metabolic changes that may accompany these pathological changes. ObjectiveThis study evaluated the predictive value of fatty acids in cerebrospinal fluid (CSF) fractions in differentiating cognitively unimpaired (CU), mild cognitive impairment (MCI), and ACD participants. MethodsCSF fatty acid profiles were analyzed from CU (n=68), MCI (n=38), and ACD (n=37) individuals aged 77.3 {+/-} 7.7 years, sourced from the Huntington Medical Research Institutes (HMRI). Multivariable binary logistic regression identified the most effective CSF fatty acid biomarkers for distinguishing CU, MCI, and ACD groups. The top-performing CSF fatty acid biomarkers were combined with A{beta}42, tau, and the A{beta}42/tau ratio to evaluate their collective diagnostic performance. The model was adjusted for covariates, including age, sex, smoking status, hypertension, diabetes, and APOE genotype. Receiver operating characteristic (ROC) curves were generated for the top 10 CSF fatty acids ranked by area under the curve (AUC), sensitivity, and specificity, and their significance was assessed using the DeLong test. ResultsThe top 10 fatty acids in CSF fractions demonstrated superior discrimination between CU individuals and those with MCI compared to traditional markers such as A{beta}42, tau, and the A{beta}42/tau ratio. Furthermore, incorporating a panel of these fatty acid biomarkers alongside A{beta}42/tau significantly improved diagnostic accuracy. Age, sex, smoking, hypertension, APOE genotype, and diabetes did not significantly influence the models performance. ConclusionThis study suggests that changes in fatty acid metabolism occur in early ACD pathology. Thus, strategies that regulate fatty acid metabolism may prevent cognitive decline in an older population. HighlightsO_LIThis study revealed that CSF fractions fatty acids have a better discriminatory power for CU from MCI than CSF A{beta}42, tau, and A{beta}42/tau ratio. C_LIO_LIA panel of CSF fraction fatty acids combined with A{beta}42/tau remarkably improved its diagnostic performance for differential diagnosis of CU, MCI, and ACD. C_LIO_LIClinical evaluation of these fatty acids will strengthen the detection of early cognitive impairment. A prospective large cohort multicenter study of the diagnostic utility of CSF fractions fatty acids will provide robust evidence before extensive clinical usage of these fatty acids. C_LI

neuroscience↗

bioRxiv2025

Altered Gut Microbiota Mediates the Association between APOE Genotype and Amyloid-β Accumulation in Middle-Aged Adults

ImportanceThe apolipoprotein E (APOE) {varepsilon}4 allele is the strongest genetic risk factor for Alzheimers disease (AD), yet the mechanisms linking APOE to amyloid-{beta} (A{beta}) pathology remain incompletely understood. Emerging evidence suggests that the gut microbiome may modulate neurodegeneration; however, its role as a mediator in the APOE-A{beta} relationship remains unclear. ObjectiveTo evaluate whether specific microbial taxa mediate APOE-related effects on brain A{beta} burden in an established population-based study of middle-aged adults. Design, Setting, and ParticipantsThis cross-sectional study analyzed data from the Framingham Heart Study cohort. Data were collected at the third examination visit (n = 227, %Female = 58, mean age = 56.5 {+/-} 8.3), between 2016 and 2019. ExposuresGut bacterial DNA was sequenced using 16S rRNA, and amplicon sequence variants (ASVs) were agglomerated at various taxonomic levels (14 phyla, 70 families, and [~]140 genera). APOE genotypes were derived from blood DNA using PCR and restriction isotyping. Predicted microbial functional potential was based on KEGG Orthologs. Main Outcomes and MeasuresOverall and regional measures of cerebral amyloid-{beta} deposition were assessed using carbon-11 Pittsburgh (PiB) Compound-B PET scans. The global PiB deposition served as the primary outcome for "overall" amyloid burden. Regional amyloid deposition values were analyzed as secondary outcomes. ResultsA higher A{beta} burden was significantly associated with the depletion of protective genera (e.g., Faecalibacterium {beta} [95%CI],-0.35 [-0.40,-0.30]; Ruminococcus-0.25 [-0.27,-0.23]; Butyricicoccus-0.27 [-0.32,-0.22]) and the enrichment of pro-inflammatory taxa (e.g., Alistipes 0.07 [0.06, 0.08], Bacteroides 0.10 [0.07, 0.13]) and Barnesiella (0.18 [0.16, 0.20]). These associations were more pronounced in APOE {varepsilon}4 carriers, who exhibited a broader spectrum of microbial dysbiosis. Mediation analysis showed that Ruminococcus, Butyricicoccus, Clostridium, and Christensenellaceae collectively mediated [~]0.3-0.4% of the effect of APOE {varepsilon}4 on global A{beta} burden. Functional profiling revealed a reduced abundance of microbial genes involved in key metabolic pathways among individuals with higher A{beta} levels. Conclusion and RelevanceGut microbiome composition partially mediates the relationship between APOE {varepsilon}4 and cerebral amyloid burden. These findings support a gut-brain axis mechanism in AD and suggest that microbiome-targeted interventions may mitigate APOE-related risk.

neuroscience↗

bioRxiv2025

Adherence to Lifes Essential 8 Enhances Gut Microbiota Diversity and Cognitive Performance

Emerging evidence suggests a complex interplay among cardiovascular health, gut microbiome composition, and cognitive function. Lifes Essential 8 (LE8), developed by the American Heart Association, includes vital metrics of cardiovascular health, such as diet, physical activity, nicotine exposure, sleep health, body mass index (BMI), blood glucose, blood lipids, and blood pressure. In this study, we analyzed data from 781 participants in the Framingham Heart Study (FHS) to explore the relationship between LE8 adherence, gut microbiota, and cognitive performance. Participants with greater adherence to LE8 demonstrated significantly increased gut microbial diversity (-diversity: Chao1, p = 0.0014; Shannon, p = 0.0071) and distinct microbial compositions ({beta}-diversity: PERMANOVA p = 1e-4). Higher adherence to LE8 was related to an increased abundance of genera Barnesiella and Ruminococcus, while a reduced abundance of Clostridium was associated with higher LE8 adherence. Greater gut microbial diversity (-diversity: Chao1, p = 0.0012; Shannon, p = 0.0066), and beneficial genera like Oscillospira correlated with better global cognitive scores (GCS). Taxonomic overlap analyses revealed microbial taxa that simultaneously influence both LE8 adherence and cognitive outcomes. Mediation analyses indicated that specific taxa, including Barnesiella and Lentisphaerae, mediated the link between LE8 adherence and cognitive performance. These taxa may serve as key modulators in the gut-brain axis, connecting cardiovascular and brain health. Conversely, higher Clostridium abundance was associated with poorer cognitive performance. This study highlights the significance of comprehensive cardiovascular health metrics in shaping gut microbiota and enhancing cognitive resilience. Our findings underscore the therapeutic potential of targeting gut microbiota to mitigate cognitive decline, warranting further exploration through longitudinal and metagenomic studies.

neuroscience↗

bioRxiv2021

Pharmacological activation of PIEZO1 in human red blood cells prevents Plasmodium falciparum invasion

An inherited gain-of-function variant (E756 del) in the mechanosensitive cationic channel PIEZO1 was recently shown to confer a significant protection against severe malaria. Here, we demonstrate in vitro that human red blood cell (RBC) infection by Plasmodium falciparum is prevented by the pharmacological activation of PIEZO1. The PIEZO1 activator Yoda1 inhibits RBC invasion, without affecting parasite intraerythrocytic growth, division or egress. RBC dehydration, echinocytosis and intracellular Na+/K+ imbalance are unrelated to the mechanism of protection. Inhibition of invasion is maintained, even after a prolonged wash out of Yoda1. Similarly, the chemically unrelated activators Jedi1 and Jedi2 potently inhibit parasitemia, further indicating a PIEZO1-dependent mechanism. Notably, Yoda1 treatment significantly reduced RBC surface receptors of P. falciparum, and decreased merozoite attachment and subsequent RBC deformation. Altogether these data indicate that the pharmacological activation of Piezo1 in human RBCs inhibits malaria infection by impairing P. falciparum invasion.

microbiology↗

bioRxiv2019

The roles of microtubules and membrane tension in axonal beading, retraction, and atrophy

Axonal beading--formation of a series of swellings along the axon--and retraction are commonly observed shape transformations that precede axonal atrophy in Alzheimers, Parkinson, and other neurodegenerative conditions. The mechanisms driving these morphological transformations are poorly understood. Here we report controlled experiments which can induce either beading or retraction and follow the time evolution of these responses. By making quantitative analysis of the shape modes under different conditions, measurement of membrane tension, and using theoretical considerations, we argue that membrane tension is the main driving force that pushes cytosol out of the axon when microtubules are degraded, causing axonal thinning. Under pharmacological perturbation, atrophy is always retrograde and this is set by a gradient in the microtubule stability. The nature of microtubule depolymerization dictates the type of shape transformation vis a vis beading or retraction. Elucidating the mechanisms of these shape transformations will facilitate development of strategies to prevent or arrest axonal atrophy due to neurodegenerative conditions.

biophysics↗