2022 Annual Meeting

Aggregation Propensity and Kinetics of Microtubule-Associated Tau Protein

Alzheimer's Disease (AD) is a neurodegenerative disease that causes a decrease in cognitive and motor skill functioning due to cell death in the frontal cortex of the brain. Tau protein is a structural component of the microtubules found in neurons and studies have shown that tau plays an important role in the development of AD. Tau aggregates can form, which is when tau is no longer bound to the microtubules and instead bound to itself, the cell loses its structural stability leading to cell death. While it is known that tau aggregates initiate AD, there are still many uncertainties and unknowns regarding tau aggregation prevention and if possible, a reversal of aggregation.

Additionally, there are several different isoforms of tau that can be present in the brain, each have their own unique properties and aggregation mechanisms. This study focused on three forms: 0N4R, VPR, and K18. 0N4R is wild type tau and the most common form of tau found in the brain. VPR is similar to wildtype but it contains three point mutations which other studies have found to increase aggregation propensity. Lastly, K18 is a fragmented version of wild-type tau, only containing the 4 repeating regions of 0N4R which is the microtubule-binding region. This study aimed to compare the speed of which each isoform would aggregate and the overall amount of aggregates formed. The protein was recombinantly produced through E.Coli cells, purified, then aggregation was induced in vitro using a known chemical aggregation inducer called heparin. Aggregation was observed using a fluorescence well-plate reader.

Overall, the study demonstrated that the fragmented tau (K18) aggregated quicker than mutated tau (VPR) and 0N4R did not aggregate at all. This is an important finding as it illustrates a clear correlation between small protein size and aggregation propensity. There also was a correlation between the mutations present and increasing aggregation speed. These findings help expand the understanding of tau protein aggregation and can be used to aid in the development of a treatment or cure for Alzheimer’s Disease.