RT Journal Article
SR Electronic
T1 Regulation of Presynaptic Ca<sup>2+</sup>, Synaptic Plasticity and Contextual Fear Conditioning by a N-terminal β-Amyloid Fragment
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 14210
OP 14218
DO 10.1523/JNEUROSCI.0326-14.2014
VO 34
IS 43
A1 Lawrence, James L.M.
A1 Tong, Mei
A1 Alfulaij, Naghum
A1 Sherrin, Tessi
A1 Contarino, Mark
A1 White, Michael M.
A1 Bellinger, Frederick P.
A1 Todorovic, Cedomir
A1 Nichols, Robert A.
YR 2014
UL http://www.jneurosci.org/content/34/43/14210.abstract
AB 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.