Do Tau Deposits Affect Blood Oxygen Supply to the Brain?

The aim of this project is to determine if deposits of tau, a key Alzheimer’s disease protein, block blood delivery of oxygen in the brain.

Tau is an important protein in Alzheimer’s disease. It can undergo changes that lead it to clump together inside nerve cells, inhibiting their function. In this innovative study, Sung Ji Ahn, PhD, and her colleagues plan to assess whether these clumps also interfere with blood flow in the brain, depriving cells of the oxygen and nutrients they need to function.

Using a lab model of Alzheimer’s disease, the researchers will first apply cutting-edge brain imaging to follow the behavior and function of cells in the brain. They expect to determine whether the spread of tau tangling through brain cells and blood vessel dysfunction are related.

With this information, they next will examine whether oxygen treatments change these patterns for the better. Improvements could signal an opening to related therapies that counteract brain dysfunction related to tau accumulation.

This study focuses on tau which will lead to a more comprehensive assessment of the molecular drivers of neurovascular dysfunction in Alzheimer’s disease and related dementias and their pathogenic consequences. Furthermore, our studies are conceptually innovative in that they will test novel hypothesis on: (a) the link between pathogenic tau, neurovascular dysfunction, and aberrant network activity, and (b) the combination of tau-induced network hyperactivity and suppression of functional hyperemia leading to reduced brain oxygen, which may aggravate tau pathology and cause brain dysfuction.

The proposed research is translationally relevant because it may provide the mechanistic bases and proof-of-principle evidence for new approaches to mitigate the deleterious effects of pathogenic tau by restoring neuronal nitric oxide production and by rescuing the oxygen deficit with supplemental oxygen. Therefore, the findings of the proposed studies, in addition to enhancing the mechanistic understanding of neurovascular dysfunction in Alzheimer’s disease and related dementias, may also point to new therapeutic avenues to counteract pathogenic tau induced cognitive dysfunction.