title: The diarylheptanoid (+)-aR,11S-myricanol and two flavones from bayberry (Myrica cerifera) destabilize the microtubule-associated protein tau.
abstract: Target-based drug discovery for Alzheimer's disease (AD) centered on modulation of the amyloid β peptide has met with limited success. Therefore, recent efforts have focused on targeting the microtubule-associated protein tau. Tau pathologically accumulates in more than 15 neurodegenerative diseases and is most closely linked with postsymptomatic progression in AD. We endeavored to identify compounds that decrease tau stability rather than prevent its aggregation. An extract from Myrica cerifera (bayberry/southern wax myrtle) potently reduced both endogenous and overexpressed tau protein levels in cells and murine brain slices. The bayberry flavonoids myricetin and myricitrin were confirmed to contribute to this potency, but a diarylheptanoid, myricanol, was the most effective anti-tau component in the extract, with potency approaching the best targeted lead therapies. (+)-aR,11S-Myricanol, isolated from M. cerifera and reported here for the first time as the naturally occurring aglycone, was significantly more potent than commercially available (±)-myricanol. Myricanol may represent a novel scaffold for drug development efforts targeting tau turnover in AD.
authors.affiliation: Department of Molecular Medicine, University of South Florida, Tampa, Florida 33613, United States.
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Jones
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Lebar
authors.forename: Umesh K
authors.initials: UK
authors.lastname: Jinwal
authors.forename: Jose F
authors.initials: JF
authors.lastname: Abisambra
authors.forename: John
authors.initials: J
authors.lastname: Koren
authors.forename: Laura
authors.initials: L
authors.lastname: Blair
authors.forename: John C
authors.initials: JC
authors.lastname: O'Leary
authors.forename: Zachary
authors.initials: Z
authors.lastname: Davey
authors.forename: Justin
authors.initials: J
authors.lastname: Trotter
authors.forename: Amelia G
authors.initials: AG
authors.lastname: Johnson
authors.forename: Edwin
authors.initials: E
authors.lastname: Weeber
authors.forename: Christopher B
authors.initials: CB
authors.lastname: Eckman
authors.forename: Bill J
authors.initials: BJ
authors.lastname: Baker
authors.forename: Chad A
authors.initials: CA
authors.lastname: Dickey
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy*; D000818:Animals; D036381:Diarylheptanoids / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D005260:Female; D005419:Flavonoids / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D006367:HeLa Cells; D006801:Humans; D008297:Male; D051379:Mice; D008954:Models, Biological; D031641:Myrica / Q000737:chemistry*; D018517:Plant Roots / Q000737:chemistry; D016548:Prosencephalon / Q000166:cytology / Q000187:drug effects; D016875:tau Proteins / Q000032:analysis / Q000187:drug effects / Q000378:metabolism*
chemical_list: D036381:Diarylheptanoids; D005419:Flavonoids; D016875:tau Proteins; C041794:myricanol; C008577:myricitrin; C040015:myricetin