Alzheimer’s Disease Tau Consortium: Post-Translational Modifications and Tau Ultrastructure; Impact of Amyloid Beta on Tau In Vivo

Alzheimer’s disease (AD) is characterized by the accumulation in the brain of two types of abnormal proteins: amyloid beta (Aβ) in the form of amyloid plaques and tau in the form of neurofibrillary tangles. The accumulation of abnormal (‘pathological’) tau is thought to be toxic to vulnerable brain cells, but the earliest events that lead to toxic tau production are not well understood. Pathological Aβ accumulation is believed to occur before tau, but how the two proteins interact is also not well understood. Many cell and mouse models have been created to examine these events, but the data from them does not truly represent what happens in the human brain as the models make too much protein too quickly, and it is often not of the type found in the human AD brain. In the first round of this grant, we developed better mouse models to explore the earliest stages of tau and Aβ accumulation. Our aims and objectives, both for round one and going forward to round 2, are to determine how and why tau becomes abnormal and toxic, how it contributes to cell dysfunction and degeneration, and how the Aβ and tau pathways interact.