Work

Fibrillar tau alters cerebral endothelial cell metabolism, vascular inflammatory activation, and barrier function in vitro and in vivo

Year: 2025

Type: article

Abstract: INTRODUCTION: The presence of tau aggregates in and around the brain vasculature in Alzheimer's disease (AD) and tauopathies suggests its possible pathogenicity to cerebral endothelial cells (ECs). METHODS: We used an in vitro model of the blood-brain barrier (BBB) to understand the mechanisms of fibrillar tau-mediated cerebral EC and BBB pathology, confirming our findings in 3-month-old P301S mice brains and extracted microvessels. RESULTS: Protofibrillar and fibrillar tau species induce endothelial barrier permeability through an increase in glycolysis, which activates ECs toward a pro-inflammatory phenotype, inducing loss of junction protein expression and localization. The Warburg-like metabolic shift toward glycolysis and increased vascular pathological phenotypes are also present in young P301S mice. DISCUSSION: In sum, our work reveals that fibrillar tau species, by enhancing endothelial glycolytic metabolism, promote vascular inflammatory phenotypes and loss of BBB function, highlighting the importance of addressing and targeting early tau-mediated neurovascular damage in AD and tauopathies. HIGHLIGHTS: We improve the understanding of the mechanisms of vascular pathology in tauopathies. Fibrillar tau mediates vascular metabolic changes, inflammation, and blood-brain barrier (BBB) dysfunction. These events are replicated at early stages in a tauopathy mouse model. Inhibiting altered glycolysis reduces BBB permeability and endothelial activation.

Source: Alzheimer s & Dementia

DOI: 10.1002/alz.70077

Authors: Roberto Guzmán‐Hernández, Silvia Fossati

Institution: Temple University

Language: English

Topic: Barrier Structure and Function Studies

Subfield: Neurology

Field: Neuroscience

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: hybrid

Estimated APC paid: $4,200