N-terminal beta amyloid fragments regulate nicotinic acetylcholine receptors

Abstract

Soluble β-amyloid (Aβ) has been shown to regulate both presynaptic Ca2+ and synaptic plasticity. In particular picomolar concentrations of Aβ were 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 have found that a functional N-terminal domain containing two histidine residues exists within Aβ that accounts for its agonist-like activity. This sequence corresponds to an N-terminal fragment generated by the combined action of α-and β-secretases, and a resident carboxypeptidase. The N-terminal Aβ fragment is present in the brains and CSF of healthy adults as well as Alzheimer's patients. Unlike full-length Aβ, the N-terminal Aβ fragment is monomeric and nontoxic. In Ca2+ imaging studies using a model reconstituted rodent neuroblastoma cell line and isolated mouse hippocampal nerve terminals, the N-terminal Aβ fragment proved to be highly potent and more effective than full-length Aβ in its agonist-like action on nicotinic receptors. In addition, the N-terminal Aβ fragment augmented theta burst-induced post-tetanic potentiation and LTP in mouse hippocampal slices. The N-terminal Aβ fragment also rescued LTP inhibited by elevated levels of full-length Aβ. Contextual fear conditioning was also strongly augmented following bilateral injection of N-terminal Aβ 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 Aβ fragment appears to reside in a sequence surrounding a putative metal binding site at its the C-terminal region, YEVHHQ. This sequence is sufficient to both produce the aforementioned agonist-like action on nicotinic receptors in our rodent neuroblastoma cell line and augment fear conditioning in our mouse model. In addition to either the basic or aromatic properties, of the two histidine residues in the sequence it also appears that the aromatic properties of the initial tyrosine are required for the activity. These finding suggest that the N-terminal Aβ fragment may serve as a potent and effective endogenous neuromodulator.