Small Molecule Approaches for Targeting Tau in Alzheimer’s Disease

Alzheimer's disease is a major cause of dementia globally and is characterized by the pathological accumulation of aggregated and hyperphosphorylated tau proteins within neurons. Tau is a microtubule-associated protein that contributes to neuronal function, allowing vesicular transport, maintenance of cellular structure and neuronal communication. Diseases in which tau is involved in a pathological process are called tauopathies and Alzheimer's takes part of this category. The number of people suffering from dementia and Alzheimer's is projected to rise considerably in the coming years, therefore the search for an effective treatment is increasingly becoming necessary. To date, there is no approved small molecule compound that can act as a disease-modifying treatment for this disease. This experimental study focuses on the biophysical characterization of synthetic pharmacological compounds able to modulate tau protein aggregation in Alzheimer´s disease, through a drug screening approach. Using various experiments, which concern tau liquid-liquid phase separation, aggregation kinetics and direct binding to the Tau protein, different compounds were tested with the aim of identifying potential therapeutic candidates able to interfere with tauopathies. Results indicate that there are structure-activity relationships underlying the binding between small molecules and Tau. Using microscopy analyses, it has been confirmed that as the structure of the drug changes, its pharmacological action on Tau condensates changes. It has also been demonstrated, through an in vitro aggregation assay, that the tested small molecules have a strong impact on Tau fibril formation, slowing down and reducing aggregation. Finally, using nuclear magnetic resonance spectroscopy, the influence of the compounds in the interaction between Tau and microtubules has been analyzed, and it has emerged that some of the tested compounds do not alter physiological Tau-microtubule binding. The knowledge gained in this study constitutes a promising path towards the development of a cure for Alzheimer's and other related tauopathies.