Characterization of a Novel Tau Aggregation Inhibitor Isolated from Fungal Secondary Metabolites

Abstract

Alzheimer’s disease is the 6th leading cause of death in the U.S. and the cost of care is billions of dollars per year. Tau aggregation is a pathological hallmark in neurodegenerative diseases known as tauopathies, which includes Alzheimer’s disease. Currently there are no approved drugs that can inhibit or reverse tau aggregation. Natural products, such as ones attained from fungi, have been utilized directly as drugs or more commonly as chemical scaffolds to produce biomedically relevant compounds. Previously it was found that secondary metabolites produced from Aspergillus nidulans were capable of inhibiting tau aggregation and provided a new chemical scaffold that was used to semi-synthetically produce compounds known as azaphilones. In the present study, more secondary metabolites produced from Aspergillus nidulans were provided to find novel chemical scaffolds that had tau aggregation inhibition (TAI) activity. One compound in particular, ANTC 15, stood out because it was structurally similar to the azaphilones but had an isoquinoline core structure. ANTC 15 was tested for TAI activity and it could inhibit the formation of tau aggregates and disassemble previously formed aggregates in vitro.