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Regulation of presynaptic Ca2+, synaptic plasticity and contextual fear conditioning by a N-terminal β-amyloid fragment
Journal article   Open access   Peer reviewed

Regulation of presynaptic Ca2+, synaptic plasticity and contextual fear conditioning by a N-terminal β-amyloid fragment

James L M Lawrence, Mei Tong, Naghum Alfulaij, Tessi Sherrin, Mark Contarino, Michael M White, Frederick P Bellinger, Cedomir Todorovic and Robert A Nichols
The Journal of neuroscience, v 34(43), pp 14210-14218
22 Oct 2014
DOI: https://doi.org/10.1523/JNEUROSCI.0326-14.2014
PMID: 25339735
Featured in Collection :   UN Sustainable Development Goals @ Drexel
url
https://doi.org/10.1523/jneurosci.0326-14.2014View
Published, Version of Record (VoR)CC BY-NC-SA V4.0,  Open
url
https://doi.org/10.1523/JNEUROSCI.0326-14.2014View
Published, Version of Record (VoR) Open

Abstract

Amino Acid Sequence Amyloid beta-Peptides - pharmacology Amyloid beta-Peptides - physiology Animals Calcium - physiology Cell Line, Tumor Conditioning (Psychology) - drug effects Conditioning (Psychology) - physiology Fear - drug effects Fear - physiology Hippocampus - drug effects Hippocampus - physiology Male Mice Mice, Inbred C57BL Mice, Transgenic Molecular Sequence Data Neuronal Plasticity - drug effects Neuronal Plasticity - physiology Organ Culture Techniques Presynaptic Terminals - drug effects Presynaptic Terminals - physiology
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.

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Collaboration types
Domestic collaboration
Web of Science research areas
Neurosciences
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