Novel A-seco-nortriterpenoids from Ganoderma cochlear inhibiting Tau pathology by activating AMPK-ULK1-mediated autophagy

Abstract

Ten structurally diverse Ganoderma triterpenoids, including one unprecedented highly degraded A-seco-nortriterpenoid, ganolearin A (1) with a 6/6/5-tricyclo structure containing a unique benzene ring, three new rearranged nortriterpenoids, ganolearin B (2) and ganolearin C (3) with a rare 3/5/6/5-fused skeleton, and ganolearin D (4) featuring a 3 → 10 γ-lactone ring and a five-membered carbon ring, and six analogues, ganolearates E–G and J (5–7, 10), and ganolearic acids H (8) and I (9), were isolated from the fruiting bodies of Ganoderma cochlear. Their structures were elucidated by extensive 1D and 2D NMR spectroscopy, HRESIMS, X-ray crystallography and ECD calculation analysis. A plausible biosynthetic pathway for 1–4 was proposed. Furthermore, compounds 1–4 significantly inhibited Tau pathology by inducing autophagy mediated by the AMPK-ULK1 pathway, suggesting their potential against Alzheimer's disease (AD).