2024 BIST Ignite Project: MAPtoFinAD

Project overview

Alzheimer’s Disease (AD) can begin up to twenty years before symptoms appear, and significant efforts are underway to detect patients earlier, while the damage is still reversible. However, successful early intervention requires a better understanding of the cell biology at these early stages.

An important path to generating this deeper understanding is through studying Tau, one of two proteins found to aggregate in AD. In healthy neurons, Tau interacts transiently with axonal microtubules. However, how Tau transitions from its role as a microtubule-associated protein (MAP), to forming solid fibers in AD—and the immediate consequences of this transition for motor-based transport in axons—remain unresolved.

MAPtoFinAD aims to develop the first in vitro reconstituted model that mimics Tau’s initial solid transition in neurons. The project team will generate dynamic microtubule bundles coated with Tau and induce its solid transition using pathological Tau conformers. As proof of concept, the team will investigate how this transition affects motor displacement and how Tau phosphorylation influences its initial solid transition.

The project will benefit from the collaborative efforts of the Surrey laboratory at CRG—whose expertise includes in vitro reconstitution of microtubule biology and motor-based transport, and Amayra Hernández-Vega and Lorena Ruiz Pérez at IBEC—whose work on the cell biology and physics of Tau aggregation will be instrumental in generating this model.

In the long term, this model is expected to help find therapeutic strategies that target Tau’s initial solid transition while preserving its function as a MAP, ultimately aiming to stop the early stages of this devastating disease.