Rapid Discovery of Aβ42 Fibril Disintegrators from Ganoderma lucidum via Ligand Fishing and Their Neuroprotective Effects on Alzheimer’s Disease

An amyloid-β (Aβ) fibril is a vital pathogenic factor of Alzheimer's disease (AD). Aβ fibril disintegrators possess great potential to be developed into novel anti-AD agents. Here, a ligand fishing method was employed to rapidly discover Aβ₄₂ fibril disintegrators from Ganoderma lucidum using Aβ₄₂ fibril-immobilized magnetic beads, which led to the isolation of six Aβ₄₂ fibril disintegrators including ganodermanontriol, ganoderic acid DM, ganoderiol F, ganoderol B, ganodermenonol, and ergosterol. Neuroprotective evaluation in vitro exhibited that these Aβ₄₂ fibril disintegrators could significantly mitigate Aβ₄₂-induced neurotoxicity. Among these six disintegrators, ergosterol and ganoderic acid DM with stronger protecting activity were further selected to evaluate their neuroprotective effect on AD in vivo. Results showed that ergosterol and ganoderic acid DM could significantly alleviate Aβ₄₂-induced cognitive dysfunction and hippocampus neuron loss in vivo. Moreover, ergosterol and ganoderic acid DM could significantly inhibit Aβ₄₂-induced neuron apoptosis and Nrf2-mediated neuron oxidative stress in vitro and in vivo.