%0 Journal Article %A James L.M. Lawrence %A Mei Tong %A Naghum Alfulaij %A Tessi Sherrin %A Mark Contarino %A Michael M. White %A Frederick P. Bellinger %A Cedomir Todorovic %A Robert A. Nichols %T Regulation of Presynaptic Ca2+, Synaptic Plasticity and Contextual Fear Conditioning by a N-terminal β-Amyloid Fragment %D 2014 %R 10.1523/JNEUROSCI.0326-14.2014 %J The Journal of Neuroscience %P 14210-14218 %V 34 %N 43 %X Soluble β-amyloid has been shown to regulate presynaptic Ca2+ 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 Ca2+ 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. %U https://www.jneurosci.org/content/jneuro/34/43/14210.full.pdf