Abstract
The aggregation of the microtubule-associated protein tau is a significant
event in many neurodegenerative diseases including Alzheimerʼs disease. The
inhibition or reversal of tau aggregation is therefore a potential
therapeutic strategy for these diseases. Fungal natural products have proven
to be a rich source of useful compounds having wide varieties of biological
activity. We have screened Aspergillus nidulans secondary metabolites
containing aromatic ring structures for their ability to inhibit tau
aggregation in vitro using an arachidonic acid polymerization
protocol and the previously identified aggregation inhibitor emodin as a
positive control. While several compounds showed some activity,
2,ω-dihydroxyemodin, asperthecin, and asperbenzaldehyde were potent
aggregation inhibitors as determined by both a filter trap assay and
electron microscopy. In this study, these three compounds were stronger
inhibitors than emodin, which has been shown in a prior study to inhibit the
heparin induction of tau aggregation with an IC50 of 1–5 µM.
Additionally, 2,ω-dihydroxyemodin, asperthecin, and asperbenzaldehyde
reduced, but did not block, tau stabilization of microtubules.
2,ω-Dihydroxyemodin and asperthecin have similar structures to
previously identified tau aggregation inhibitors, while asperbenzaldehyde
represents a new class of compounds with tau aggregation inhibitor activity.
Asperbenzaldehyde can be readily modified into compounds with strong
lipoxygenase inhibitor activity, suggesting that compounds derived from
asperbenzaldehyde could have dual activity. Together, our data demonstrates
the potential of 2,ω-dihydroxyemodin, asperthecin, and
asperbenzaldehyde as lead compounds for further development as therapeutics
to inhibit tau aggregation in Alzheimerʼs disease and neurodegenerative
tauopathies.
Key words
tau - microtubule-associated protein - Trichocomaceae -
Aspergillus nidulans
- Alzheimerʼs disease
