title: Decreased accumulation of subcellular amyloid-β with improved mitochondrial function mediates the neuroprotective effect of huperzine A.
abstract: A number of recent discoveries indicate that huperzine A, an active herbal medicine employed for the treatment of Alzheimer's disease (AD) in China, can afford neuroprotection on in vitro and in vivo models related to mitochondrial dysfunction. However, it is an intricate and highly debated research topic about whether another pharmacological mechanism is involved in the beneficial profiles of huperzine A, independent of its well-recognized potent acetycholinesterase (AChE) inhibitory effect. As an extension, this study for the first time verified the co-occurrence of the beneficial effects of huperzine A on mitochondrial dysfunction and memory deficits in AβPP/PS1 double transgenic mice, at a time point that AChE was not inhibited. Moreover, using isolated brain cortical mitochondria, we confirmed the ameliorating effect of huperzine A on oligomeric Aβ1-42-induced ATP reduction and mitochondrial swelling, as well as a decrease in the enzymatic activities of respiratory chain complexes, especially complex II-III and complex IV, which may be attributed to the blockage of oligomeric Aβ1-42 from penetrating into mitochondria. These results shed more light on a potential direct target of huperzine A on isolated mitochondria, which may be largely different from its specific inhibition on AChE. This work describes a novel mechanism of neuroprotection by huperzine A and provides important clues for discovering novel therapeutic strategy for AD.
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Ling
authors.initials: L
authors.lastname: Yang
authors.forename: Chun-Yan
authors.initials: CY
authors.lastname: Ye
authors.forename: Xiao-Tian
authors.initials: XT
authors.lastname: Huang
authors.forename: Xi-Can
authors.initials: XC
authors.lastname: Tang
authors.forename: Hai-Yan
authors.initials: HY
authors.lastname: Zhang
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000470:Alkaloids / Q000627:therapeutic use*; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism* / Q000494:pharmacology; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D002540:Cerebral Cortex / Q000473:pathology* / Q000648:ultrastructure; D002800:Cholinesterase Inhibitors / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D046529:Microscopy, Electron, Transmission; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D009097:Multienzyme Complexes / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D010446:Peptide Fragments / Q000494:pharmacology; D053764:Presenilin-1 / Q000235:genetics; D012717:Sesquiterpenes / Q000627:therapeutic use*
chemical_list: D000470:Alkaloids; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D002800:Cholinesterase Inhibitors; D009097:Multienzyme Complexes; C508853:PSEN1 protein, human; D010446:Peptide Fragments; D053764:Presenilin-1; D012717:Sesquiterpenes; C075222:amyloid beta-protein (1-42); C050426:huperzine A; D000255:Adenosine Triphosphate; D000110:Acetylcholinesterase