title: The Ca(2+) channel inhibitor 2-APB reverses β-amyloid-induced LTP deficit in hippocampus by blocking BAX and caspase-3 hyperactivation.
abstract: OBJECTIVE
  At the early stage of Alzheimer's disease (AD), the accumulation of β-amyloid (Aβ) oligomers disturbs intracellular Ca(2+) homeostasis and disrupts synaptic plasticity of brain neurons. Prevention of Aβ-induced synaptic failure remains an unsolved problem for the treatment of AD. Here, the effects of 2-aminoethoxydiphenyl borate (2-APB), a non-specific, but moderately potent Ca(2+) channel inhibitor, on Aβ-induced deficit of synaptic long-term potentiation (LTP) and the underlying molecular mechanisms were explored.
  
  
  METHODS
  We used hippocampal slices and primary cultures of hippocampal neurons from C57BL/6 mice. Methods applied in our study included electrophysiological recording, membrane protein extraction, Western blot assay and Ca(2+) imaging.
  
  
  RESULTS
  2-APB at 10 μM effectively reversed suppression by oligomeric Aβ1-42 (500 nM) of LTP in hippocampal slices. 2-APB also restored phosphorylation and trafficking of the glutamate receptor subunit GluA1 in Aβ-treated hippocampal slices, supporting its protective action on synaptic function. Aβ-mediated abnormal neuronal [Ca(2+) ]i elevation and hyperactivation of the mitochondrial apoptotic proteins BAX, caspase-3, and glycogen synthase kinase-3β, were blocked by 2-APB pretreatment. Moreover, the defict in long term potentiation deficit in hippocampal slices from APPswe /PS1ΔE 9 gene mutant mice was rescued by 2-APB at 10 μM.
  
  
  CONCLUSIONS
  These data demonstrate that 2-APB is a potentially useful chemical to protect synaptic plasticity against neurotoxic effects of Aβ in AD.
authors.affiliation: The Key Laboratory of Stem Cell and Regenerative Medicine, Institute of Molecular and Clinical Medicine, Kunming Medical University, Kunming, China; Shunxi-Monash Immune Regeneration and Neuroscience Laboratories, Department of Anatomy and Developmental Biology, Monash University, Melbourne, Australia; School of Pharmaceutical Science and Yunnan Key Laboratory of Pharmacology for Natural Products, Kunming Medical University, Kunming, China.
authors.forename: Wei-Yan
authors.initials: WY
authors.lastname: Hu
authors.forename: Zhi-Yong
authors.initials: ZY
authors.lastname: He
authors.forename: Lu-Jun
authors.initials: LJ
authors.lastname: Yang
authors.forename: Ming
authors.initials: M
authors.lastname: Zhang
authors.forename: Da
authors.initials: D
authors.lastname: Xing
authors.forename: Zhi-Cheng
authors.initials: ZC
authors.lastname: Xiao
mesh_terms: D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D001896:Boron Compounds / Q000494:pharmacology*; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D020013:Calcium Signaling / Q000187:drug effects*; D053148:Caspase 3 / Q000378:metabolism*; D002478:Cells, Cultured; D004789:Enzyme Activation; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006624:Hippocampus / Q000187:drug effects* / Q000201:enzymology; D066298:In Vitro Techniques; D017774:Long-Term Potentiation / Q000187:drug effects*; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D010446:Peptide Fragments / Q000494:pharmacology*; D010766:Phosphorylation; D053764:Presenilin-1 / Q000235:genetics; D061251:Primary Cell Culture; D021381:Protein Transport; D018091:Receptors, AMPA / Q000187:drug effects / Q000378:metabolism; D013569:Synapses / Q000187:drug effects* / Q000201:enzymology; D013997:Time Factors; D051028:bcl-2-Associated X Protein / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D001896:Boron Compounds; D002121:Calcium Channel Blockers; D053148:Caspase 3; D038362:Glycogen Synthase Kinase 3; D000071679:Glycogen Synthase Kinase 3 beta; D010446:Peptide Fragments; D053764:Presenilin-1; D018091:Receptors, AMPA; D051028:bcl-2-Associated X Protein; C494827:Bax protein, mouse; C075222:amyloid beta-protein (1-42); C580804:presenilin 1, mouse; C109986:2-aminoethoxydiphenyl borate; C000605507:Gsk3b protein, mouse; C505409:Casp3 protein, mouse