Tau Oligomers and Their Potential Role in Toxicity Leading to Alzheimer's Disease
Tau is one of the main proteins that is responsible for causing Alzheimer's disease (AD). Tau can have many different structures and we would like to identify the structure that leads to AD. If we are successful in doing so, we believe we can then target these particular structures for therapy.
This grant was transferred to Dr. Nicholas M. Kanaan upon the passing of the original PI, Dr. Lester "Skip" Binder in November 2013. The research project is being continued in Skip's memory.
Upon completion of this project, we hope to show that tau oligomers are the toxic tau species involved in Alzheimer’s disease and other tauopathies. The tau protein exists within humans as six different isoforms (versions), varying in length and composition. Dr. Binder’s team is testing the hypothesis that each of these forms of the tau aggregate, and that different aggregation conditions can lead the proteins to form into different structures (called oligomers or filaments). Recently, evidence suggests that neurofibrillary tangles (NFTs) may not be responsible for causing toxicity within the brain. Dr. Binder’s laboratory generated two novel antibodies (TOC1 and TNT1) to help them to investigate whether all oligomers are toxic. The team will assess how well each antibody binds to each species of tau aggregate. TOC1 is selective for tau oligomers only, and TNT1 binds to a sticky region of tau protein, called the PAD region, which is unmasked in the diseased brain. They will examine TOC1 and TNT1’s relative affinities for oligomers purified from the brains donated by late patients who had AD, Progressive Supranuclear Palsy (PSP) and Corticobasal Degeneration (CBD). Since we are the only one with access to both these antibodies, we feel we have the necessary tools to investigate this important question.
Secondly, Dr. Binder’s team is investigating whether all tau oligomers are toxic. Following purification of oligomers, the team will use a special test, called the cell viability assay, to monitor for cell death. This will be extended further, with toxicity testing also being carried out by collaborators at Woods Hole, MA. This will allow the team to investigate if these oligomers are having an effect on an internal nerve cell protein transport process called Fast Axonal Transport (FAT), since inhibition of FAT is a hallmark of AD.
Recently tau oligomers have gained a lot of attention, and Dr. Binder’s team possesses unique tools—the TOC1 and TNT1 antibodies—that could be used for high-throughput screens for drugs, peptides, or small molecule compounds which could prevent oligomerization of the tau protein, and prevent unmasking of the PAD domain, thereby alleviating toxicity. Prevention of these abnormal changes in tau could inhibit the signaling cascade that leads to defects in FAT in patients with tauopathies (diseases like AD, CBD, and PSP).
Dr. Binder’s team strongly believes that tau oligomers are the toxic tau species thought to be responsible for the neurodegeneration found in many tauopathies. Although oligomers formed in each of the numerous tauopathies are likely somewhat diverse in structure, the team’s TOC1 antibody has thus far recognized tau oligomers in AD, PSP, CBD, and Chronic traumatic encephalopathy (CTE, as can be found in the brains of NFL players). The proposed studies should give clues as to the conformation of the toxic aggregate and its region of toxicity.