Aβ Oligomers and the Pathogenic Spread of Tau Aggregation: Implications for Alzheimer’s Disease Mechanism and Treatment

The goal of this project is to conduct a series of experiments designed to elucidate the role of Abeta and exosomes (vesicles involved in “cell-to-cell signaling”) in the transfer of Tau clumps from nerve cell to nerve cell.

Two proteins are known to be critically involved in Alzheimer’s disease: Abeta and Tau. Both are prone to “self-associate,” such that in the Alzheimer brain clumps of Abeta, known as amyloid plaques, are found in the spaces in between nerve cells and clumps of Tau, known as neurofibrillary tangles, are found within nerve cells. Until recently it was assumed that Abeta had to form plaques to be toxic; however, it is now clear that smaller, mobile clumps of Abeta (referred to as oligomers) are also damaging. When Dr. Walsh’s lab isolated an oligomer from a human brain composed of just two Abeta molecules (referred to as Abeta dimer) and injected it into rats, it caused amnesia. Studies also show that lowering Tau levels can protect nerve cells against the toxic effects of Abeta oligomers. These data indicate that Abeta oligomers cause changes in Tau that harm brain cells. In parallel, evidence has emerged that clumps of Tau can be passed from one nerve cell to another. Indeed this process may explain why neurofibrillary tangles appear to spread through the brain as the disease progresses.

Thus understanding how Tau pathology is “transmitted” and, if Abeta is involved, should identify novel targets for therapeutic intervention. For instance, if Abeta is found to cause the release of Tau via small membranous vesicles known as exosomes, it should be possible to prevent either the release of Tau-containing exosomes or their uptake by unaffected recipient cells. If this is possible, drugs designed to prevent the spread of Tau pathology should halt further cognitive deterioration. Accordingly, this project will include a series of experiments designed to elucidate the role of Abeta and exosomes in the transfer of Tau clumps from nerve cell to nerve cell.