title: The experimental Alzheimer's disease drug posiphen [(+)-phenserine] lowers amyloid-beta peptide levels in cell culture and mice.
abstract: Major characteristics of Alzheimer's disease (AD) are synaptic loss, cholinergic dysfunction, and abnormal protein depositions in the brain. The amyloid beta-peptide (Abeta), a proteolytic fragment of amyloid beta precursor protein (APP), aggregates to form neuritic plaques and has a causative role in AD. A present focus of AD research is to develop safe Abeta-lowering drugs. A selective acetylcholinesterase inhibitor, phenserine, in current human trials lowers both APP and Abeta. Phenserine is dose-limited in animals by its cholinergic actions; its cholinergically inactive enantiomer, posiphen (+)-[phenserine], was assessed. In cultured human neuroblastoma cells, posiphen, like phenserine, dose- and time-dependently lowered APP and Abeta levels by reducing the APP synthesis rate. This action translated to an in vivo system. Posiphen administration to mice (7.5-75 mg/kg daily, 21 consecutive days) significantly decreased levels of total APP (tissue mass-adjusted) in a dose-dependent manner. Abeta40 and Abeta42 levels were significantly lowered by posiphen (> or =15 mg/kg) compared with controls. The activities of alpha-, beta-, and gamma-secretases were assessed in the same brain samples, and beta-secretase activity was significantly reduced. Posiphen, like phenserine, can lower Abeta via multiple mechanisms and represents an interesting drug candidate for AD treatment.
authors.affiliation: Institute of Psychiatric Research, Department of Psychiatry, Indiana University School of Medicine, 791 Union Drive, Indianapolis, IN 46202, USA. dlahiri@iupui.edu
authors.forename: Debomoy K
authors.initials: DK
authors.lastname: Lahiri
authors.forename: DeMao
authors.initials: D
authors.lastname: Chen
authors.forename: Bryan
authors.initials: B
authors.lastname: Maloney
authors.forename: Harold W
authors.initials: HW
authors.lastname: Holloway
authors.forename: Qian-sheng
authors.initials: QS
authors.lastname: Yu
authors.forename: Tada
authors.initials: T
authors.lastname: Utsuki
authors.forename: Tony
authors.initials: T
authors.lastname: Giordano
authors.forename: Kumar
authors.initials: K
authors.lastname: Sambamurti
authors.forename: Nigel H
authors.initials: NH
authors.lastname: Greig
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy*; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000032:analysis*; D016564:Amyloid beta-Protein Precursor / Q000032:analysis / Q000235:genetics; D000818:Animals; D045744:Cell Line, Tumor; D002540:Cerebral Cortex / Q000737:chemistry / Q000187:drug effects; D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010830:Physostigmine / Q000031:analogs & derivatives* / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis; D013237:Stereoisomerism
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D002800:Cholinesterase Inhibitors; D012333:RNA, Messenger; D010830:Physostigmine; D053829:Amyloid Precursor Protein Secretases; C092280:phenserine