The abnormal aggregation of the microtubule-associated protein tau is closely linked to neuronal death and subsequent cognitive deficits in Alzheimer’s disease and other related neurodegenerative diseases. The inhibition and reversal of tau aggregation is believed to be a significant target for the development of therapeutic strategies to treat such disorders. In our efforts to identify tau aggregation inhibitors (TAIs), we have sought to explore the secondary metabolome of the fungus Aspergillus nidulans for unique compounds with anti-tau aggregation properties. Fungal natural products have historically been a rich source of biologically important compounds ranging from anti-cholesterol medications to antibiotics. By screening just a small library of A. nidulans natural products, we were able to identify three lead compounds capable of inhibiting tau aggregation. One of these, asperbenzaldehyde, represented a novel class of TAI. Because asperbenzaldehyde is a precursor to the chemical class of azaphilones, we subsequently generated and analyzed the TAI activity of 11 azaphilone derivatives in vitro. We found that all azaphilone derivatives tested inhibited tau aggregation. Four of the compounds also caused the disassembly of pre-formed filaments in a dose-dependent fashion by reducing both the length and number of tau filaments. Tau also retained significant microtubule-stabilization activity even in the presence of the most potent TAI, indicating that azaphilone scaffold may be a very promising structural core for future development of tau therapeutics and that the A. nidulans secondary metabolome is a rich resource for the further discovery of TAIs.

Fungal metabolome as a rich resource for tau aggregation inhibitors

251st National Meeting (2016)

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