Optogenetic model of tau aggregation for tauopathies

Abstract

AbstractBackgroundAlzheimer’s disease (AD) and >20 other dementias, termed tauopathies, are pathologically defined by insoluble aggregates of the microtubule‐associated protein tau (MAPT). A predictive relationship between the onset and progression of clinical AD symptoms correlates with post‐translational modifications of tau in cerebrospinal fluid and tau aggregation in the brains of AD patients. However, the biological basis for the transition of tau from a microtubule‐associated protein to an insoluble aggregate and the precise relationship between tau aggregation and neuronal dysfunction remains unknown. Recent studies have reported the development of photo‐inducible systems to control protein aggregation using photo‐oligomerizable proteins that self‐associate upon exposure to blue light. We hypothesized that the development of a photo‐inducible system, which permits temporal control of tau aggregation, would provide a novel tool to study the cause and consequence of tau aggregation.MethodsWe fused Vivid (VVD), a photoreceptor that self‐associates upon exposure to blue light, to full‐length (2N4R) tau, termed optoTAU. In addition, we generated optoTAU plasmids that contain other MAPT isoforms (e.g., 0N4R, 1N4R) and pro‐ and anti‐aggregation mutations in MAPT. We investigated the effect of blue stimulation on the soluble and insoluble aggregation of optoTAU in a cellular and neuronal model by immunoblot and immunocytochemical analysis.ResultsOptoTAU permits temporal control of tau aggregation that faithfully reproduces the isoform‐specific and dementia‐associated aggregation properties of tau. OptoTAU provides a platform to visualize the transition of tau from a soluble to an insoluble aggregate in a cellular model of tau aggregation.ConclusionsOptoTAU is a biologically‐relevant model to investigate modifiers of tau pathobiology in AD and other tauopathies and is a drug discovery platform to identify pharmacological modifiers of tau aggregation.