Basic Science and Pathogenesis.

Area of Science:

• Neuroscience
• Vascular Biology
• Cell Biology

Background:

• Aggregated tau protein can spread throughout the brain, potentially causing cerebrovascular and neurovascular unit dysfunction.
• The mechanisms by which tau affects endothelial cells (ECs) are not well understood, but are crucial for understanding early vascular changes in neurodegeneration.
• Protofibrillar tau induces inflammation and metabolic changes in ECs, impairing barrier function.

Purpose of the Study:

• To investigate the role of the receptor for advanced glycation end-products (RAGE) and advanced glycation end products (AGEs) in tau-induced EC dysfunction.
• To determine if inhibiting RAGE or AGE production can prevent tau-mediated damage to the endothelial barrier.

Main Methods:

• Human brain microvascular ECs were exposed to protofibrillar tau and treated with RAGE inhibitors or AGE scavengers.
• RAGE knockout ECs were used to assess the direct role of RAGE.
• Measurements included trans-endothelial electrical resistance (TEER) for barrier integrity, cytokine production for inflammation, and EC bioenergetics.
• Western blotting was used to detect protein levels of VCAM-1, RAGE, and tau.

Main Results:

• Protofibrillar tau reduced TEER and increased glycolysis, leading to a proinflammatory EC phenotype, which was reversed by metabolic modulation.
• RAGE inhibition decreased tau entry into ECs, reversed inflammation, and prevented barrier dysfunction and metabolic changes.
• Inhibiting tau-mediated AGE production also prevented barrier loss and increased glycolysis.
• RAGE deletion protected ECs from barrier and metabolic damage.

Conclusions:

• Fibrillar tau activates RAGE signaling, causing EC barrier dysfunction and inflammation.
• Tau-mediated AGE production acts as an intermediate, sustaining RAGE activation and metabolic alterations.
• These findings elucidate mechanisms of tau-induced EC dysfunction, highlighting RAGE and AGEs as potential therapeutic targets.