Exploration of multi-target effects of 3-benzoyl-5-hydroxychromen-2-one in Alzheimer's disease cell and mouse models

Aging Cell. 2020 Jul;19(7):e13169. doi: 10.1111/acel.13169. Epub 2020 Jun 4.


Microtubule-associated protein Tau, abundant in the central nervous system (CNS), plays crucial roles in microtubule assembly and stabilization. Abnormal Tau phosphorylation and aggregation are a common pathogenic hallmark in Alzheimer's disease (AD). Hyperphosphorylation of Tau could change its conformation and result in self-aggregation, increased oxidative stress, and neuronal death. In this study, we examined the potential of licochalcone A (a natural chalcone) and five synthetic derivatives (LM compounds) for inhibiting Tau misfolding, scavenging reactive oxygen species (ROS) and providing neuroprotection in human cells expressing proaggregant ΔK280 TauRD -DsRed. All test compounds were soluble up to 100 μM in cell culture media and predicted to be orally bioavailable and CNS-active. Among them, licochalcone A and LM-031 markedly reduced Tau misfolding and associated ROS, promoted neurite outgrowth, and inhibited caspase 3 activity in ΔK280 TauRD -DsRed 293 and SH-SY5Y cells. Mechanistic studies showed that LM-031 upregulates HSPB1 chaperone, NRF2/NQO1/GCLC pathway, and CREB-dependent BDNF/AKT/ERK/BCL2 pathway in ΔK280 TauRD -DsRed SH-SY5Y cells. Decreased neurite outgrowth upon induction of ΔK280 TauRD -DsRed was rescued by LM-031, which was counteracted by knockdown of NRF2 or CREB. LM-031 further rescued the downregulated NRF2 and pCREB, reduced Aβ and Tau levels in hippocampus and cortex, and ameliorated cognitive deficits in streptozocin-induced hyperglycemic 3 × Tg-AD mice. Our findings strongly indicate the potential of LM-031 for modifying AD progression by targeting HSPB1 to reduce Tau misfolding and activating NRF2 and CREB pathways to suppress apoptosis and promote neuron survival, thereby offering a new drug development avenue for AD treatment.

Keywords: Alzheimer's disease; LM-031; Tau; apoptosis; chaperone; oxidative stress.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / drug therapy*
  • Animals
  • Apoptosis
  • Disease Models, Animal
  • Humans
  • Male
  • Mice
  • Oxidative Stress
  • Up-Regulation