Biology subjects

Kavanagh, T.

Publications and source records attributed to Kavanagh, T..

4 recordsLinked to original sources

bioRxiv2026

Seeding patient-derived tau induces tauopathy-specific aggregation and lysosomal disruption in human cells

BackgroundTau aggregation is the defining feature of tauopathies, however, the mechanisms by which distinct tau strains drive disease-specific responses remain unclear. Existing models largely rely on recombinant tau seeding or tau overexpression, which fail to capture the biochemical diversity of pathological tau. The aim of this study was to develop a robust and reproducible human cell-based model of disease-specific tau pathology and to use this model to determine how tau from unique diseases impact tau accumulation and lysosomal dysfunction. MethodsPatient-derived tau aggregates were enriched from post-mortem brain tissue obtained from sporadic Alzheimers disease (AD), Picks disease (PiD), progressive supranuclear palsy (PSP), and control cases using phosphotungstic acid precipitation. Patient-derived tau preparations were biochemically characterised by immunoblotting and mass spectrometry and normalised for tau content prior to seeding. Patient-derived tau aggregates were seeded into multiple human immortalised cell lines (SH-SY5Y, M03.13, U-87 MG, and U-118 MG cells) and iPSC-derived astrocytes. Tau seeding efficiency, aggregate morphology, and integrity of the autophagy-lysosomal pathway was assessed using quantitative imaging approaches. ResultsPatient-derived tau seeds retained disease-specific phosphorylation patterns and isoform composition and led to reproducible, dose-dependent insoluble tau accumulation in all cell lines tested. Despite equivalent tau input and similar background protein composition, PiD-derived tau had the most aggressive pathological signature, showing the highest number of tau aggregates per cell and inducing system wide disruptions in the autophagy lysosomal system including increased SQSTM1 puncta and lysosomal damage markers. Seeding with AD-derived tau led to a high number of tau aggregates per cell and more specifically depleted the lysosomal protease CTSD and uniquely co-seeded A{beta} pathology. Seeding with PSP-derived tau resulted in only a moderate number of tau aggregates per cell and uniquely caused increased lysosomal biogenesis. ConclusionsTogether, these results demonstrate that intrinsic properties of human tau strains drive disease-specific cellular responses and establish a scalable, physiologically relevant platform for dissecting tau-cell interactions and screening therapeutics across tauopathies.

cell biology↗

bioRxiv2025

Targeting intracellular tau with a gene-encoded single-chain antibody promotes neuronal homeostasis and ameliorates tau pathology

The intraneuronal aggregation of tau is a key driver of pathogenesis in Alzheimer's disease and other tauopathies. The positively charged proline-rich region and microtubule-binding domain of tau are important for tubulin binding which enables axonal transport in physiological conditions. In disease, however, the positively charged repeat domains of such regions become exposed, facilitating tau-tau aggregation and other pathogenic tau-protein interactions which leads to neuronal dysfunction. Here, we generated a polyanionic peptide to electrostatically interact with tau and fused it to an inert single-chain variable fragment (scFv) antibody for improved peptide half-life and downstream intraneuronal expression. The resultant polyanionic peptibody, ACR12, was investigated in vitro and in tau transgenic mice for ability to prevent tau aggregation and associated disease phenotypes. In human neuroblastoma cells, ACR12 was stably expressed within the cytoplasm where it successfully engaged intracellular tau. DNA encoding ACR12 was then packaged into a brain-penetrant Adeno-associated virus, AAV-PHP.eB, for intravenous delivery into K3 tau transgenic mice. Such treatment facilitated long-term intraneuronal expression of ACR12 and reduced total and phosphorylated tau in the brain. ACR12 treatment in female K3 mice also restored deregulated neuronal proteins to wild-type levels. This study highlights the role of positively charged domains in tau pathogenesis and demonstrates the therapeutic utility of electrostatic tau interactors.

neuroscience↗

bioRxiv2025

VISIBLE: An imaging-driven system for sampling, biofabrication, and manipulation of complex biological models

Complex in vitro models (CIVMs), including organoids, spheroids, and bioprinted constructs, have emerged as powerful platforms for recapitulating human tissue architecture and function. However, their inherent heterogeneity and dynamic nature pose significant challenges for standardization, reproducibility, and real-time manipulation. Here, we present VISIBLE (Versatile Imaging-Based Interactive Sampling and Bioprinting System), a modular, imaging-guided platform that integrates real-time monitoring with automated manipulation and 3D bioprinting that addresses these challenges. VISIBLE employs a dual-axis system comprising independently controlled tool-heads and microscope stages, enabling precise spatiotemporal interventions within live cultures. We demonstrate the system capabilities across a range of applications, including morphology- and function-based sampling of organoids and neurospheres, interactive 3D bioprinting, serial scratch assays, and real-time cell-cell interaction studies. Furthermore, we illustrate the system utility in translational contexts through the selective sampling and implantation of patient-derived xenograft organoids. VISIBLE supports long-term culture within an integrated incubation environment and accommodates interchangeable tool-heads for scalable, high-throughput workflows. By enabling closed-loop, feedback-controlled experimentation, VISIBLE addresses some of the critical limitations in existing CIVM platforms and offers a new versatile solution for a wide range of biomedical research applications. This work represents a significant step toward the development of autonomous experimental systems for complex tissue modelling and preclinical investigation.

bioengineering↗

bioRxiv2023

Compilation of all known protein changes in the human Alzheimer's disease brain

Proteomic studies of human Alzheimers disease brain tissue have exceptional potential to identify protein changes that drive disease and to identify new drug targets. Here, we detail a combined analysis of 38 published Alzheimers disease proteomic studies, generating a comprehensive map of protein changes in human brain tissue across thirteen brain regions, three disease stages (preclinical Alzheimers disease, mild cognitive impairment, advanced Alzheimers disease), and proteins enriched in amyloid plaques, neurofibrillary tangles, and cerebral amyloid angiopathy. Our dataset is compiled into a user-friendly, searchable database called NeuroPro. Our combined analysis included 18,119 reported protein differences in human Alzheimers disease brain tissue, which mapped to 5,311 total altered proteins. Proteomic studies were remarkably consistent. 848 proteins were consistently altered in [≥]5 studies, many of which are understudied in the Alzheimers field. Comparison of protein changes in early-stage and advanced Alzheimers disease revealed significant synapse, vesicle, and lysosomal changes early in disease, but widespread mitochondrial changes only in advanced Alzheimers disease. Comparison of vulnerable and resistant brain regions suggested that protein changes in resistant regions in advanced Alzheimers disease are similar to those in vulnerable regions in early-stage Alzheimers disease, indicating a temporal progression of protein dysfunction during Alzheimers disease advancement. We conclude that NeuroPro is a powerful new resource that provides new insights into human Alzheimers disease brain protein changes and highlights novel proteins of particular interest that may mechanistically drive Alzheimers disease.

neuroscience↗