BACKGROUND: Aggregation of misfolded amyloid β (Aβ) in senile plaques causes oxidative stress and neuronal death in Alzheimer's disease (AD). Compounds possessing antiaggregation and antioxidant properties are promising candidate compounds for AD treatment. METHODS: We examined the potential of synthetic derivatives of licochalcone A and coumarin for inhibiting Aβ aggregation, scavenging reactive oxygen species (ROS), and providing neuroprotection by using biochemical assays and Tet-On Aβ-GFP 293/SH-SY5Y cell models for AD. RESULTS: Among test compounds, LM-031, a novel chalcone-coumarin hybrid, inhibited Aβ aggregation and scavenged free oxygen radicals. LM-031 markedly reduced Aβ misfolding and ROS as well as promoted neurite outgrowth and inhibited acetylcholinesterase in Tet-On Aβ-GFP 293/SH-SY5Y cells. Mechanistic studies showed upregulation of the HSPB1 chaperone, NRF2/NQO1/GCLC pathway, and CREB/BDNF/BCL2 pathway. Decreased neurite outgrowth upon the induction of Aβ-GFP was rescued by LM-031, which was counteracted by knockdown of HSPB1, NRF2, or CREB. CONCLUSION: Taken together, these findings demonstrate that LM-031 exhibited antiaggregation, antioxidant, and neuroprotective effects against Aβ toxicity by enhancing HSPB1 and the NRF2-related antioxidant pathway as well as by activating the CREB-dependent survival and antiapoptosis pathway. These results imply that LM-031 may be a new therapeutic compound for AD.
BACKGROUND: Aggregation of misfolded amyloid β (Aβ) in senile plaques causes oxidative stress and neuronal death in Alzheimer's disease (AD). Compounds possessing antiaggregation and antioxidant properties are promising candidate compounds for AD treatment. METHODS: We examined the potential of synthetic derivatives of licochalcone A and coumarin for inhibiting Aβ aggregation, scavenging reactive oxygen species (ROS), and providing neuroprotection by using biochemical assays and Tet-On Aβ-GFP 293/SH-SY5Y cell models for AD. RESULTS: Among test compounds, LM-031, a novel chalcone-coumarin hybrid, inhibited Aβ aggregation and scavenged free oxygen radicals. LM-031 markedly reduced Aβ misfolding and ROS as well as promoted neurite outgrowth and inhibited acetylcholinesterase in Tet-On Aβ-GFP 293/SH-SY5Y cells. Mechanistic studies showed upregulation of the HSPB1 chaperone, NRF2/NQO1/GCLC pathway, and CREB/BDNF/BCL2 pathway. Decreased neurite outgrowth upon the induction of Aβ-GFP was rescued by LM-031, which was counteracted by knockdown of HSPB1, NRF2, or CREB. CONCLUSION: Taken together, these findings demonstrate that LM-031 exhibited antiaggregation, antioxidant, and neuroprotective effects against Aβ toxicity by enhancing HSPB1 and the NRF2-related antioxidant pathway as well as by activating the CREB-dependent survival and antiapoptosis pathway. These results imply that LM-031 may be a new therapeutic compound for AD.
Authors: A E Reyes; D R Perez; A Alvarez; J Garrido; M K Gentry; B P Doctor; N C Inestrosa Journal: Biochem Biophys Res Commun Date: 1997-03-27 Impact factor: 3.575
Authors: K Itoh; T Chiba; S Takahashi; T Ishii; K Igarashi; Y Katoh; T Oyake; N Hayashi; K Satoh; I Hatayama; M Yamamoto; Y Nabeshima Journal: Biochem Biophys Res Commun Date: 1997-07-18 Impact factor: 3.575
Authors: D Schubert; C Behl; R Lesley; A Brack; R Dargusch; Y Sagara; H Kimura Journal: Proc Natl Acad Sci U S A Date: 1995-03-14 Impact factor: 11.205