Biology subjects

Properzi, M.

Publications and source records attributed to Properzi, M..

3 recordsLinked to original sources

bioRxiv2025

Blood-based Transcriptomics Reveal Sex- and Amyloid-Modulated Biology of Plasma pTau217 in Preclinical Alzheimer's Disease

Plasma pTau217, an emerging Alzheimers disease (AD) biomarker, may reflect a synaptic response to {beta}-amyloid (A{beta}) plaques before cortical tangle formation, but its broader biological correlates remain unclear. We sought to identify associations between whole blood gene expression and plasma pTau217, and to determine whether APOE{varepsilon}4, sex, and neocortical A{beta}-PET modify these associations in 724 participants from the Anti-Amyloid Treatment in Asymptomatic Alzheimers and accompanying LEARN studies (A4/LEARN, Agemean(SD)=72.2(4.6); 63%female). Of 20,621 genes tested (1,048 X-linked), none were directly associated with pTau217; one gene was moderated by APOE{varepsilon}4, 1,540 genes by A{beta}-PET, and 772 genes by both A{beta}-PET and sex. Over 100 of these significant associations were X-linked, supporting a role of the X chromosome in AD. Sex interactions were only observed in the presence of elevated A{beta}-PET. Our results underscore the complexity of molecular mechanisms that can be linked to plasma pTau217, particularly in the context of elevated A{beta}-PET.

neuroscience↗

bioRxiv2024

Building a model of sepsis: data integration unravels pathogenic mechanisms in severe P. aeruginosa infections.

Understanding host-pathogen interactions is crucial for explaining the variability in sepsis outcomes, with Pseudomonas aeruginosa (PA) remaining a significant public health concern. In this work, we explored PA-human host interaction mechanisms through a data integration workflow, focusing on protein-protein and metabolite-protein interactions, along with pathway modulation in affected organs during severe infections. A scoping literature review enabled us to construct a domain-based infection network encompassing pathogenesis concepts, molecular interactions, and host response signatures, providing a wide view of the relevant mechanisms involved in severe bacterial infections. Our analysis yielded a literature-based comprehensive description of PA infection mechanisms and an annotated dataset of 189 PA-human interactions involving 152 proteins/molecules (109 human proteins, 3 human molecules, 34 PA proteins, and 5 PA molecules). This dataset was complemented with gene expression analysis from in vivo PA-infected lung samples. The results indicated a notable overexpression of proinflammatory pathways and PA-mediated modulation of host lung responses. Our comprehensive molecular network of PA infection represents a valuable tool for the understanding of severe bacterial infections and offers potential applications in predicting clinical phenotypes. Through this approach combining omics data, clinical information, and pathogen characteristics, we have provided a foundation for future research in host-pathogen interactions and the mechanistic grounds to build dynamic computational models for clinical phenotype predictions.

systems biology↗

bioRxiv2020

Genetic Variants and Functional Pathways Associated with Resilience to Alzheimer's Disease

Approximately 30% of older adults exhibit the neuropathologic features of Alzheimers disease (AD) without signs of cognitive impairment. Yet, little is known about the genetic factors that allow these potentially resilient individuals to remain cognitively normal in the face of substantial neuropathology. We performed a large, genome-wide association study (GWAS) of two previously validated metrics of cognitive resilience quantified using a latent variable modeling approach and representing better-than-predicted cognitive performance for a given level of neuropathology. Data were harmonized across 5,108 participants from a clinical trial of AD and three longitudinal cohort studies of cognitive aging. All analyses were run across all participants and repeated restricting the sample to individuals with normal cognition to identify variants at the earliest stages of disease. As expected, all resilience metrics were genetically correlated with cognitive performance and education attainment traits (p-values<2.5x10-20), and we observed novel correlations with neuropsychiatric conditions (p-values<7.9x10-4). Notably, neither resilience metric was genetically correlated with clinical AD (p-values>0.42) nor associated with APOE (p-values>0.13). In single variant analyses, we observed a genome-wide significant locus among participants with normal cognition on chromosome 18 upstream of ATP8B1 (index SNP rs2571244, MAF=0.08, p=2.3x10-8). The top variant at this locus (rs2571244) was significantly associated with methylation in prefrontal cortex tissue at multiple CpG sites, including one just upstream of ATPB81 (cg19596477; p=2x10-13). Overall, this comprehensive genetic analysis of resilience implicates a putative role of vascular risk, metabolism, and mental health in protection from the cognitive consequences of neuropathology, while also providing evidence for a novel resilience gene along the bile acid metabolism pathway. Furthermore, the genetic architecture of resilience appears to be distinct from that of clinical AD, suggesting that a shift in focus to molecular contributors to resilience may identify novel pathways for therapeutic targets.

genetics↗