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

Soluble beta-amyloid has been shown to regulate presynaptic Ca2+ and synaptic plasticity. In particular, picomolar beta-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 beta-amyloid for its agonist-like activity. This sequence corresponds to a N-terminal fragment generated by the combined action of alpha- and beta-secretases, and resident carboxypeptidase. The N-terminal beta-amyloid fragment is present in the brains and CSF of healthy adults as well as in Alzheimer's patients. Unlike full-length beta-amyloid, the N-terminal beta-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 beta-amyloid fragment proved to be highly potent and more effective than full-length beta-amyloid in its agonist-like action on nicotinic receptors. In addition, the N-terminal beta-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 beta-amyloid. Contextual fear conditioning was also strongly augmented following bilateral injection of N-terminal beta-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 beta-amyloid fragment appears to reside largely in a sequence surrounding a putative metal binding site, YEVHHQ. These findings suggest that the N-terminal beta-amyloid fragment may serve as a potent and effective endogenous neuromodulator.