Search bioRxiv⌕ Search
Home/Archive/bioRxiv

bioRxiv · 10.1101/2024.09.24.613639

Neuropathological evidence of reduced amyloid beta and neurofibrillary tangles in multiple sclerosis cortex

Pansieri, J.·Pisa, M.·Yee, S.·Gutnikova, A.·Ridgeon, E.·Hickman, R.·Spencer, J. I.·Esiri, M. M.·DeLuca, G. C.
View original source ↗Export metadata ↓

Abstract

Multiple sclerosis (MS) and Alzheimers disease (AD) are neurodegenerative diseases demonstrating age-related accumulation of disability. Inflammation lasting decades is a paradigmatic feature of MS pathology that variably relates to neurodegeneration, while the accumulation of A{beta} plaques and neurofibrillary tangles (NFT) are cornerstones of AD pathology. However, few studies investigated the accumulation of amyloids in MS. We investigated A{beta} deposition and NFT density in temporal or frontal cortices derived from a large post-mortem cohort of MS (n=78) and age and sex-matched control (n=65) cases. We found reduced A{beta} burden in MS cases compared with controls, particularly in cases below 65-years-of-age. NFT were similarly reduced in MS compared to controls, notably in cases above 65 years-of-age. Higher A{beta} deposition predicted greater NFT density in MS. These findings suggest that MS-related factors may influence A{beta} and NFT deposition and/or clearance. This work highlights new therapeutic perspectives relevant for both MS and AD.

Source connections

Explore related subjects

pathologyPreprint

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

Pansieri, J., Pisa, M., Yee, S., Gutnikova, A., Ridgeon, E., Hickman, R., Spencer, J. I., Esiri, M. M., DeLuca, G. C.. 2024-09-25. Neuropathological evidence of reduced amyloid beta and neurofibrillary tangles in multiple sclerosis cortex. https://doi.org/10.1101/2024.09.24.613639

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

NAE1-Dependent Protein Neddylation Preserves Endothelial Identity and Vascular Integrity

Background: Endothelial dysfunction is a central driver of cardiovascular and inflammatory diseases, yet the post-translational mechanisms that preserve endothelial homeostasis remain incompletely understood. Protein neddylation, the covalent conjugation of a ubiquitin-like modifier, regulates diverse cellular processes, yet its physiological role in the vascular endothelium remains unknown. This study investigated whether protein neddylation is required to preserve endothelial identity and vascular homeostasis. Methods: We generated tamoxifen-inducible endothelial-specific Nae1 knockout mice to inhibit neddylation and combined bulk RNA sequencing, single-cell and single-nucleus transcriptomics, quantitative proteomics, biochemical analyses, and gain- and loss-of-function approaches to define the role of endothelial neddylation in vascular homeostasis and inflammatory injury. Results: Endothelial-specific Nae1 deletion caused rapid mortality associated with vascular leakage, platelet accumulation, inflammation, and multi-organ injury. Multi-omics analyses demonstrated profound loss of endothelial identity, characterized by suppression of core endothelial programs and activation of inflammatory, procoagulant, and pyroptotic pathways. Single-cell analyses revealed progressive endothelial dysfunction culminating in depletion of the endothelial population and remodeling of the vascular niche. Mechanistically, endothelial neddylation deficiency activated gasdermin D (GSDMD)- and gasdermin E (GSDME)-dependent pyroptosis, whereas dual inhibition of GSDMD and GSDME markedly attenuated inflammatory transcriptomic remodeling, vascular injury, hepatocyte death, immune cell infiltration, and platelet accumulation. Translational analyses demonstrated reduced endothelial neddylation in experimental endotoxemia and decreased expression of neddylation pathway components in human atherosclerosis and COVID-19 datasets. Conversely, restoration of endothelial neddylation partially reversed inflammatory endothelial transcriptomic reprogramming in vivo. Conclusions: NAE1-dependent protein neddylation is an essential regulator of endothelial identity and vascular integrity. Loss of endothelial neddylation promotes gasdermin-dependent pyroptosis and thrombo-inflammatory vascular injury, whereas restoration of the neddylation pathway mitigates inflammatory endothelial dysfunction. These findings identify endothelial neddylation as a fundamental mechanism maintaining vascular homeostasis and a potential therapeutic target for cardiovascular and inflammatory diseases.

pathology↗
bioRxiv2024

Targeting STING in experimental peritoneal damage: a novel approach in peritoneal dialysis therapy

Peritoneal dialysis (PD) is a widely used kidney replacement therapy for end-stage kidney disease (ESKD) patients. However, long-term exposure to PD fluids (PDF) can lead to peritoneal membrane (PM) damage, causing ultrafiltration failure and thus PD discontinuation. Investigating the molecular mechanisms underlying this damage is crucial for identifying new therapeutic targets to mitigate peritoneal deterioration in PD patients. Therefore, in this work we study the role of STING in peritoneal inflammation and fibrosis. To this aim, we performed different preclinical mouse models of peritoneal inflammation, fibrosis, and adhesions. In a chlorhexidine gluconate (CHX)-induced inflammation model, we found changes in the peritoneal transcriptomic profile, and cytosolic DNA-sensing signaling was one of the most enriched KEGG pathways. STING, as a conspicuous member of this pathway, was upregulated in CHX-and PDF-exposed mice, and in peritoneal biopsies from PD patients. STING genetic deficiency diminished peritoneal inflammation, by downregulating inflammatory gene expression, preventing NF-{kappa}B pathway activation, and decreasing cell infiltration, in early (10 days) and advanced (30 days) stages of the CHX model. STING absence also decreased PM thickness and fibrosis in the advanced CHX model, reduced adhesion scores in a post-surgical intra-abdominal adhesion model, and decreased inflammation in an S. epidermidis-induced peritonitis model. Furthermore, pharmacological inhibition of STING with C-176 decreased inflammation and macrophage-mediated mesothelial-to-mesenchymal transition in cultured mesothelial cells, and reduced CHX-induced PM thickness and inflammation in mice. Altogether, these findings highlight STING as a key mediator of peritoneal damage and suggest it may be a novel therapeutic target for preventing PD-associated peritoneal deterioration.

pathology↗
bioRxiv2024

A histomorphological atlas of resected mesothelioma from 3446 whole-slide images discovered by self-supervised learning

1Mesothelioma is a highly lethal and poorly biologically understood disease which presents diagnostic challenges due to its morphological complexity. This study uses self-supervised AI (Artificial Intelligence) to map the histomorphological landscape of the disease. The resulting atlas consists of recurrent patterns identified from 3446 Hematoxylin and Eosin (H&E) stained images scanned from resected tumour slides. These patterns generate highly interpretable predictions, achieving state-of-the-art performance with 0.65 concordance index (c-index) for outcomes and 88% AUC in subtyping. Their clinical relevance is endorsed by comprehensive human pathological assessment. Furthermore, we characterise the molecular underpinnings of these diverse, meaningful, predictive patterns. Our approach both improves diagnosis and deepens our understanding of mesothelioma biology, highlighting the power of this self-learning method in clinical applications and scientific discovery.

pathology↗