title: Bis(7)-tacrine attenuates beta amyloid-induced neuronal apoptosis by regulating L-type calcium channels.
abstract: Beta amyloid protein (Abeta) and acetylcholinesterase (AChE) have been shown to be closely implicated in the pathogenesis of Alzheimer's disease. In the current study, we investigated the effects of bis(7)-tacrine, a novel dimeric AChE inhibitor, on Abeta-induced neurotoxicity in primary cortical neurons. Bis(7)-tacrine, but not other AChE inhibitors, elicited a marked reduction of both fibrillar and soluble oligomeric forms of Abeta-induced apoptosis as evidenced by chromatin condensation and DNA specific fragmentation. Both nicotinic and muscarinic receptor antagonists failed to block the effects of bis(7)-tacrine. Instead, nimodipine, a blocker of L-type voltage-dependent Ca2+ channels (VDCCs), attenuated Abeta neurotoxicity, whereas N-, P/Q- or R-type VDCCs blockers and ionotropic glutamate receptor antagonists did not. Fluorescence Ca2+ imaging assay revealed that, similar to nimodipine, bis(7)-tacrine reversed Abeta-triggered intracellular Ca2+ increase, which was mainly contributed by the extracellular Ca2+ instead of endoplasmic reticulum and mitochondria Ca2+. Concurrently, using whole cell patch-clamping technique, it was found that bis(7)-tacrine significantly reduced the augmentation of high voltage-activated inward calcium currents induced by Abeta. These results suggest that bis(7)-tacrine attenuates Abeta-induced neuronal apoptosis by regulating L-type VDCCs, offers a novel modality as to how the agent exerts neuroprotective effects.
authors.affiliation: Department of Biochemistry, Hong Kong University of Science and Technology, Hong Kong, P.R. China.
authors.forename: Hongjun
authors.initials: H
authors.lastname: Fu
authors.forename: Wenming
authors.initials: W
authors.lastname: Li
authors.forename: Yuanzhi
authors.initials: Y
authors.lastname: Lao
authors.forename: Jialie
authors.initials: J
authors.lastname: Luo
authors.forename: Nelson T K
authors.initials: NT
authors.lastname: Lee
authors.forename: Kelvin K W
authors.initials: KK
authors.lastname: Kan
authors.forename: Hing Wai
authors.initials: HW
authors.lastname: Tsang
authors.forename: Karl W K
authors.initials: KW
authors.lastname: Tsim
authors.forename: Yuanping
authors.initials: Y
authors.lastname: Pang
authors.forename: Zhiwang
authors.initials: Z
authors.lastname: Li
authors.forename: Donald C
authors.initials: DC
authors.lastname: Chang
authors.forename: Mingtao
authors.initials: M
authors.lastname: Li
authors.forename: Yifan
authors.initials: Y
authors.lastname: Han
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000704:Analysis of Variance; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020746:Calcium Channels, L-Type / Q000502:physiology*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology*; D002800:Cholinesterase Inhibitors; D000077265:Donepezil; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004622:Embryo, Mammalian; D006624:Hippocampus / Q000166:cytology; D007189:Indans / Q000494:pharmacology; D007531:Isoflurophate / Q000494:pharmacology; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000187:drug effects*; D009553:Nimodipine / Q000494:pharmacology; D018408:Patch-Clamp Techniques / Q000379:methods; D010446:Peptide Fragments / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D051381:Rats; D013619:Tacrine / Q000031:analogs & derivatives* / Q000494:pharmacology; D013997:Time Factors
chemical_list: C122128:1,7-N-heptylene-bis-9,9'-amino-1,2,3,4-tetrahydroacridine; D016229:Amyloid beta-Peptides; D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D002800:Cholinesterase Inhibitors; D007189:Indans; D010446:Peptide Fragments; D010880:Piperidines; C075222:amyloid beta-protein (1-42); C074636:amyloid beta-protein (25-35); D007531:Isoflurophate; D013619:Tacrine; D009553:Nimodipine; D000077265:Donepezil; D000110:Acetylcholinesterase; D002118:Calcium