Inducing aggresome and insoluble tau aggregation using an optogenetic tool

Abstract

Tauopathy is a group of diseases where fibrillary tau aggregates are formed in neurons and glial cells in the brain. In Alzheimer's disease (AD), the most common form of tauopathy, tau aggregation begins in the brainstem and entorhinal cortex and then spreads throughout the brain. Understanding the mechanism by which locally formed tau pathology propagates throughout the brain is crucial for comprehending the pathogenesis of AD. Therefore, a novel model of tau pathology that artificially induces tau aggregation in targeted cells at specific times is essential. In this study, we report a novel optogenetic module, OptoTau, human tau with the P301L mutation fused with a photosensitive protein Cry2Olig, which could induce various forms of tau depending on the pattern of blue light illumination. Continuous blue light illumination for 12 h to Neuro2a cells stably expressing OptoTau (OptoTauKI cells) resulted in cluster formation along microtubules, many of which eventually accumulated in aggresomes. On the other hand, when alternating light exposure and darkness in 30-minute cycles for 8 sets per day were repeated over 8 days, methanol-insoluble tau aggregation was formed. Methanol-insoluble tau was induced more rapidly by repeating cycles of 5-minute illumination followed by 25 minutes of darkness over 24 hours. These findings suggest that OptoTau can induce various stages of tau aggregation depending on the pattern of blue light exposure. Thus, this technique holds promise as a novel approach to creating specific tau aggregation in targeted cells at desired time points.