Small Molecules Targeting and Modulating Toxic Tau Oligomeric Strains

Alzheimer’s disease (AD) is one of over 18 different disorders known as tauopathies, characterized by the pathological aggregation and accumulation of tau, a microtubule-associated protein. Tau aggregates are heterogeneous and can be divided into two major groups: large metastable neurofibrillary tangles (NFTs) and oligomers. Recently, it has been shown that tau oligomers are highly toxic in vitro and efficient seeds for the propagation of pathology as compared to NFTs. While the toxicity of recombinant tau oligomers has been studied extensively, within the same aggregation state, tau exhibits conformational differences, termed tau oligomeric strains. Due to the dynamic nature of these strains, little is currently known about the mechanisms underlying their formation and characteristics. Therefore, modulating their aggregation states and conformations through the use of small molecules could be a powerful therapeutic strategy that targets toxicity regardless of other factors involved in the formation of tau oligomeric strains. Herein, I used biochemical and biophysical in vitro techniques to characterize preformed tau oligomers and brain-derived tau oligomers (BDTOs) in the presence and absence of small molecules, including Azure C (AC) and newly synthesized curcumin derivatives. Interestingly, AC and curcumin analogs are able to bind and modulate tau oligomers aggregation pathways resulting in the formation of tau structures with decreased toxicity as assessed in human neuroblastoma SH-SY5Y cell line and primary cortical neuron cultures. These results provide novel insights into tau aggregation and may lead to the discovery of new compounds effective against one or more tau strains. Identification of such active compounds may lay the groundwork for developing novel therapeutic agents as well as advancing the diagnostic field for the detection of toxic tau oligomers and differential diagnosis for tauopathies.