Grant: Project Grant

Lay summary. The well-known brain deposits in Alzheimer's Disease (AD) called neurofibrillary tangles (NFT) are made of a protein called tau, while the other hallmark of AD, the plaques, are made of a different, shorter protein molecule called Abeta. While the failure of several clinical trials has led to an energetic debate as to the importance of Abeta, many labs agree that accumulation of abnormal tau in the brain leads to irrevocable cell loss and that tau can be considered as an executioner molecule. Moreover, beyond AD there are a number of other dementias that also feature abnormal tau deposits, speaking to its importance. Frontotemporal Dementia (FTD) is one case in point and the second most common dementia after AD. Our recent work focuses on a form of FTD with a cumbersome (but accurate) technical name, "FTLD-MAPT-P301L". Using frozen brain tissues, we have defined unexpected diversity in three-dimensional shape of tau protein in these patients and also the brains of a mouse model of FTLD-MAPT-P301L. The diversity may be highly relevant to the way in which FTD disease divides up into different subtypes with different clinical outcomes. We have three Aims will explore how 3D shapes of tau influence disease and might in turn define a need for different types of therapies. Aim 1. We will explore factors which might trigger the emergence of tau protein with different 3D shapes. Aim 2. We will explore how tau with incorrect 3D shape moves from brain cells to brain support cells and how incorrect 3D shapes of tau might interconvert. Aim 3. We will directly test how tau with alternative incorrect 3D shapes defines different types of dementia seen in a clinic by introducing misshapen tau molecules into susceptible mice. This proposal will draw upon expertise in protein folding and misfolding; the expected outcomes are to decipher the origins, disease potential and therapeutic vulnerability of different tau dementias.