title: Regulation of presynaptic Ca2+, synaptic plasticity and contextual fear conditioning by a N-terminal β-amyloid fragment.
abstract: Soluble β-amyloid has been shown to regulate presynaptic Ca(2+) and synaptic plasticity. In particular, picomolar β-amyloid was found to have an agonist-like action on presynaptic nicotinic receptors and to augment long-term potentiation (LTP) in a manner dependent upon nicotinic receptors. Here, we report that a functional N-terminal domain exists within β-amyloid for its agonist-like activity. This sequence corresponds to a N-terminal fragment generated by the combined action of α- and β-secretases, and resident carboxypeptidase. The N-terminal β-amyloid fragment is present in the brains and CSF of healthy adults as well as in Alzheimer's patients. Unlike full-length β-amyloid, the N-terminal β-amyloid fragment is monomeric and nontoxic. In Ca(2+) imaging studies using a model reconstituted rodent neuroblastoma cell line and isolated mouse nerve terminals, the N-terminal β-amyloid fragment proved to be highly potent and more effective than full-length β-amyloid in its agonist-like action on nicotinic receptors. In addition, the N-terminal β-amyloid fragment augmented theta burst-induced post-tetanic potentiation and LTP in mouse hippocampal slices. The N-terminal fragment also rescued LTP inhibited by elevated levels of full-length β-amyloid. Contextual fear conditioning was also strongly augmented following bilateral injection of N-terminal β-amyloid fragment into the dorsal hippocampi of intact mice. The fragment-induced augmentation of fear conditioning was attenuated by coadministration of nicotinic antagonist. The activity of the N-terminal β-amyloid fragment appears to reside largely in a sequence surrounding a putative metal binding site, YEVHHQ. These findings suggest that the N-terminal β-amyloid fragment may serve as a potent and effective endogenous neuromodulator.
authors.affiliation: Department of Cell and Molecular Biology, University of Hawai'i at Manoa, Honolulu, Hawaii 96813, and.
authors.forename: James L M
authors.initials: JL
authors.lastname: Lawrence
authors.affiliation: Department of Cell and Molecular Biology, University of Hawai'i at Manoa, Honolulu, Hawaii 96813, and Departments of Pharmacology and Physiology and.
authors.forename: Mei
authors.initials: M
authors.lastname: Tong
authors.affiliation: Department of Cell and Molecular Biology, University of Hawai'i at Manoa, Honolulu, Hawaii 96813, and.
authors.forename: Naghum
authors.initials: N
authors.lastname: Alfulaij
authors.affiliation: Department of Cell and Molecular Biology, University of Hawai'i at Manoa, Honolulu, Hawaii 96813, and.
authors.forename: Tessi
authors.initials: T
authors.lastname: Sherrin
authors.affiliation: Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, Pennsylvania 19102.
authors.forename: Mark
authors.initials: M
authors.lastname: Contarino
authors.affiliation: Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, Pennsylvania 19102.
authors.forename: Michael M
authors.initials: MM
authors.lastname: White
authors.affiliation: Department of Cell and Molecular Biology, University of Hawai'i at Manoa, Honolulu, Hawaii 96813, and.
authors.forename: Frederick P
authors.initials: FP
authors.lastname: Bellinger
authors.affiliation: Department of Cell and Molecular Biology, University of Hawai'i at Manoa, Honolulu, Hawaii 96813, and.
authors.forename: Cedomir
authors.initials: C
authors.lastname: Todorovic
authors.affiliation: Department of Cell and Molecular Biology, University of Hawai'i at Manoa, Honolulu, Hawaii 96813, and robert.nichols@hawaii.edu.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Nichols
mesh_terms: D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000494:pharmacology* / Q000502:physiology; D000818:Animals; D002118:Calcium / Q000502:physiology*; D045744:Cell Line, Tumor; D003213:Conditioning, Psychological / Q000187:drug effects / Q000502:physiology*; D005239:Fear / Q000187:drug effects / Q000502:physiology*; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009473:Neuronal Plasticity / Q000187:drug effects / Q000502:physiology*; D009924:Organ Culture Techniques; D017729:Presynaptic Terminals / Q000187:drug effects / Q000502:physiology*
chemical_list: D016229:Amyloid beta-Peptides; D002118:Calcium
keywords: Ca regulation; fear memory; neuromodulation; synaptic plasticity; β-amyloid