PROBING EFFECTS OF ANESTHESIA AND EXERCISE ON TAU PHOSPHORYLATION

Accumulation of p-tau, a major hallmark of Alzheimer’s Disease (AD), may begin in the entorhinal cortex (EC) already during the prodromal stages of AD. Current attempts to model this include artificial expression of different forms of human tau in rodents, but it has proven challenging to distinguish disease-relevant mechanisms from artifacts caused by the overexpression of a foreign protein. We use anesthesia and hypothermia to induce endogenous p-tau formation in rats and test the effects of high-intensity interval training (HIIT) upon such p-tau formation. We apply prolonged and repetitive isoflurane anesthesia - a clinically relevant stressor associated with accelerated neurodegenerative processes. Formation of p-tau is characterized and quantified by immunohistochemistry, and we plan to probe for possible fibrillation of tau using cryo-electron microscopy. HIIT interventions consist of treadmill-based acute or long-term exercise. We plan to test putative effects related to behavior and cognition by using novel object recognition tasks and Y-maze tests. Two results stand out so far. First, the most striking appearance of endogenous p-tau is found in ECLII, followed by ECLIII and parts of the hippocampus. Second, in accordance with prior findings, hypothermia is a major contributing factor to p-tau formation. Inducing hypothermia under anesthesia may be a convenient approach to generate endogenous p-tau formation that mimics certain aspects of the initial stages of AD. Future work will help determine which AD-relevant tau epitopes become phosphorylated with this approach, whether this is fully reversible, and whether HIIT affects such endogenous p-tau formation.