Bis(7)-tacrine attenuates β amyloid-induced neuronal apoptosis by regulating L-type calcium channels

Hongjun Fu, Wenming Li, Yuanzhi Lao, Jialie Luo, Nelson T.K. Lee, Kelvin K.W. Kan, Hing Wai Tsang, Karl W.K. Tsim, Yuanping Pang, Zhiwang Li, Donald C. Chang, Mingtao Li, Yifan Han

Research output: Contribution to journalArticlepeer-review

97 Scopus citations

Abstract

β Amyloid protein (Aβ) 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 Aβ-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 Aβ-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 Aβ 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 Aβ-triggered intracellular Ca 2+ increase, which was mainly contributed by the extracellular Ca2+ instead of endoplasmic reticulum and mitochondria Ca 2+. 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 Aβ. These results suggest that bis(7)-tacrine attenuates Aβ-induced neuronal apoptosis by regulating L-type VDCCs, offers a novel modality as to how the agent exerts neuroprotective effects.

Original languageEnglish (US)
Pages (from-to)1400-1410
Number of pages11
JournalJournal of neurochemistry
Volume98
Issue number5
DOIs
StatePublished - Sep 1 2006

Keywords

  • Apoptosis
  • Bis(7)-tacrine
  • Ca
  • L-type voltage-dependent Ca channels
  • β amyloid

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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