In Vivo Testing of Novel Tau Fibrillization Inhibitors

Progress Updates

The dementia of Alzheimer's disease (AD) is believed to be caused, at least in part, by clumps of aggregated material within nerve cells. These aggregates are made from misfolded tau protein and are referred to as neurofibrillary tangles (NFTs). The objective of this research program is to test a set of novel molecules that act to prevent the formation of NFTs. These molecules are to be tested first for their distribution and safety in healthy mice, and those molecules that enter and persist in the brain while being free of side-effects will then be tested in mice that have been engineered to form NFT-like tau aggregates like those seen in AD. If one of the tested molecules is found to prevent the formation of NFTs in these mice, this would provide important evidence that this or a related molecule (called an analogue) might serve as a future drug candidate for the treatment of AD.

In the first 10 months of this program, Dr. Brunden’s team identified molecules that have desirable properties, including good brain levels in healthy mice, which suggested that these molecules were appropriate candidates for testing in mice with AD. However, additional research into these compounds and related analogues indicated that they act by an undesirable mechanism that would likely cause side-effects upon long-term administration. Therefore, the team has halted further optimization of these compounds, and will refocus their efforts on the identification of alternative compounds that prevent tau aggregate formation in a novel cell-based model. Use of this unique cell-based assay, in which NFT-like tau aggregates develop, will allow for the discovery of molecules that can reduce NFTs through multiple mechanisms. This approach could increase the likelihood of finding compounds that might ultimately lead to AD therapeutics.