Biology subjects

da Silva, L.

Publications and source records attributed to da Silva, L..

3 recordsLinked to original sources

bioRxiv2026

Molecular mechanisms underlying amyloid lowering by aducanumab: differential and comparative effects of sex and IgG reveal the post-treatment disease brain

INTRODUCTIONImproving the predictive validity of preclinical studies for Alzheimers disease (AD) requires rigorous evaluation of therapeutic efficacy, safety, and sex-specific responses in translationally relevant models. As amyloid-targeting monoclonal antibodies continue to advance clinically, there is an urgent need to define the molecular milieu that persists after amyloid is reduced and disease progression continues. Leveraging the NIA-funded MODEL-AD Preclinical Testing Core, we investigated the biochemical, functional, and multi-omic signatures associated with chronic administration of murine chimeric aducanumab (chAdu) in 5XFAD mice, including the contribution of IgG-mediated effects. METHODSMale and female 5XFAD mice were treated weekly with chAdu beginning at 8 months of age and compared to age-and sex-matched murine IgG2a{kappa} isotype (IgG) and saline controls. Plasma and brain pharmacokinetics, amyloid-beta (A{beta}), behavioral assessments, and treatment-emergent anti-drug antibodies (ADAs) were quantified. Post-treatment transcriptomic and proteomic analyses were performed to assess molecular pathways associated with chAdu and IgG exposure following 17-week treatment. RESULTSchAdu produced sex-dependent changes in A{beta}, including increased plasma A{beta}42:40 and reductions in brain A{beta} which were associated with mild behavioral impairments in the absence of improvements in cognitive function. IgG control treatment produced similar reductions, indicating biologically active IgG-mediated processes independent of A{beta}-targeted specificity. Treatment-emergent ADAs occurred in 10% of chAdu-treated mice and were associated with reduced drug exposure and efficacy. Multi-omics analyses confirmed sex-dependent and IgG-mediated effects at both the transcriptomic and proteome level revealing disease-associated genes and proteins not altered despite reductions in amyloid with treatment. DISCUSSIONThese findings demonstrate sex-dependent PK and pharmacodynamic responses to chAdu, identify biologically meaningful IgG-driven effects, and reveal molecular signatures that persist after amyloid reduction. This work provides biological insights into pathways that may remain insufficiently addressed following amyloid lowering; revealing novel targets for future drug discovery to prevent and treat disease.

neuroscience↗

bioRxiv2025

T-cell Multiomic Analysis Identifies Subsets and Mechanisms of Interaction with Epithelial Cells in Idiopathic Pulmonary Fibrosis

Idiopathic pulmonary fibrosis (IPF) is a fatal interstitial lung disease characterized by progressive scarring and respiratory failure, with a median survival of 3-5 years. While T-cell numbers are elevated in IPF lungs, their contributions to fibrosis beyond inflammation remain poorly understood. Here, we performed multiplex imaging and single-cell RNA and protein profiling on [~]90,000 CD3 T-cells from control and fibrotic lungs, revealing eleven distinct subsets of CD4 and CD8 T-cells. Among these, we identified a rare CD56 regulatory T-cell subset that is highly activated in fibrosis and exhibits a sustained immunosuppressive phenotype. CXCR4/MIF signaling emerged as a central axis mediating T-cell-epithelial interactions, while epidermal growth factor receptor (EGFR) and TGF{beta} pathways dominated in multiple T-cell subsets. Our findings demonstrate that T-cells in IPF adopt nonclassical activation patterns, driven by epithelial interactions and the fibrotic microenvironment. These studies provide a foundation for exploring novel therapeutic strategies in IPF lungs by modulating T-cell behavior and communication networks.

immunology↗

bioRxiv2024

Maspin/SerpinB5 is a cytoskeleton-binding protein that regulates epithelial cell shape

Maspin/SerpinB5 is an abundant and pleiotropic protein mostly expressed by epithelia. Initially described as a tumor suppressor, it has been reported as a regulator of cell adhesion, migration, and invasion. How intracellular Maspin orchestrates these processes is poorly understood. In this study, we utilized Affinity purification-Mass spectrometry (AP/MS) alongside in vitro reconstitution assays to establish that Maspin directly interacts with microtubules and microfilaments. Additionally, CRISPR/Cas9-mediated GFP tagging of endogenous Maspin, combined with immunostaining, revealed its localization at the cortical cytoskeleton and the mitotic spindle. Depletion of Maspin by RNAi and CRISPR/Cas9 in three distinct epithelial cell lines disrupts cell-cell adhesion, reorganizes the cytoskeleton and results in upregulation of mesenchymal markers during interphase. In mitotic cells, loss of Maspin induces abnormal cell rounding and rearrangement of cortical F-actin. Moreover, Maspin suppresses microtubule growth in vitro and in cells. Collectively, these results demonstrate that Maspin acts at the interface between the cytoskeleton and adhesion sites, directly modulating cell shape and preventing epithelial-mesenchymal transition. SummaryDa Silva et al. report that the non-inhibitory serpin Maspin (SerpinB5), which has long been implicated in the regulation of cell adhesion, migration, invasion and metastasis, directly binds to microfilaments and microtubules in vitro and in cells, acting at the interface between the cytoskeleton and adhesion sites.

cell biology↗