Alzheimer's & dementia : the journal of the Alzheimer's AssociationMar 20, 2025

Clumped tau protein changes brain blood vessel cell metabolism, inflammation, and barrier function in lab and living models

Alzheimers & Treatments Weekly Brief ↗PubMed ↗DOI ↗OA ↗

Updated Apr 3, 2026

Abstract

species induce endothelial barrier permeability by increasing glycolysis and promoting a pro-inflammatory phenotype in cerebral endothelial cells.

Protofibrillar and fibrillar tau species are associated with increased permeability of the endothelial barrier.
This permeability is linked to enhanced glycolytic metabolism in cerebral endothelial cells.
The shift toward glycolysis is connected to a pro-inflammatory response and loss of junction protein expression.
Similar vascular pathological changes are observed in young P301S mice, suggesting early tau-mediated neurovascular damage.
Inhibiting the altered glycolysis pathway may reduce permeability and endothelial cell activation.

Simplified

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 (BBB) to understand the mechanisms of -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.

Key numbers

25 nM

Decrease in Barrier Resistance

Protofibrillar tau treatment at this concentration leads to measurable loss of barrier function.

3 hours

Increased Glycolysis

Glycolytic rates increase significantly within this time frame after tau exposure.

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Funding

Competing interests

The authors declare no conflicts of interest. Author disclosures are available in the supporting information.

PubMed

Clumped tau protein changes brain blood vessel cell metabolism, inflammation, and barrier function in lab and living models

Abstract

Key numbers

Full Text

Funding

Competing interests

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