INVESTIGATING THE POTENTIAL OF NOVEL CURCUMIN DERIVATIVES IN TARGETING AND MODULATING TOXIC TAU OLIGOMERIC STRAINS

Abstract

Tauopathies are devastating age-related neurodegenerative disorders, characterized by the pathological aggregation and accumulation of the microtubule-associated protein tau and its subsequent deposition in different aggregated forms, including neurofibrillary tangles (NFTs). Recent research suggest that NFTs are the least toxic form of tau aggregates. However, the smaller, dynamic and soluble tau oligomers have been shown to be more toxic and efficient seeds for the propagation of pathology as compared to NFTs. Tau oligomers are a heterogeneous group of biophysically and conformationally distinct tau multimers that manifest in many different conformations, termed tau oligomeric strains. Due to the dynamic nature of these strains, studies focusing on the mechanisms underlying their formation and characteristics are challenging. Importantly, different tau oligomeric strains could explain how the aggregation of the same protein causes different diseases, progression rates and phenotypes even between individuals within the same disorder. Thus, depleting the disease-relevant structures by using small molecules could be a powerful therapeutic strategy that targets toxicity regardless of other factors involved in the formation of tau oligomeric strains. Herein we screened newly synthetized curcumin-like compounds to target and modulate tau oligomeric strains toxicity. Modulating their conformations through the use of novel curcumin derivatives could be useful for the prevention of tau oligomers formation and toxicity. We used in vitro techniques such as Western Blot and direct ELISA as well as biophysical assays to characterize tau oligomeric strains and their reactivity with tau oligomer specific polyclonal and monoclonal antibodies, T22 and TOMA respectively, in the presence and absence of curcumin derivatives. Interestingly, novel curcumin derivatives bind and are capable to alter tau aggregation pathways, resulting in the formation of tau structures with decreased toxicity. Further investigations on the capability of curcumin analogs to target and modulate toxic oligomeric tau strains associated with different neurodegenerative tauopathies will deliver compelling evidence moving the tau field forward. Curcumin analogs could aid both in the development of novel therapeutic approaches for AD and other tauopathies as well as imaging agents able to detect toxic tau oligomeric strains in the early stages of the disease.