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The Journal of Neuroscience, July 30, 2003, 23(17):6740-6747

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-Amyloid Regulation of Presynaptic Nicotinic Receptors in Rat Hippocampus and Neocortex

John J. Dougherty, Jianlin Wu, and Robert A. Nichols

Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, Pennsylvania 19102

Alteration by -amyloid (A) of signaling via nicotinic acetylcholine receptors (nAChRs) has been implicated in the early stages of Alzheimer's disease. nAChRs function both post- and presynaptically in the nervous system; however, little is known about the functional consequence of the interaction of A with these receptors, particularly those on presynaptic nerve terminals. In view of the strong correlation between loss of synaptic terminals and dementia, together with the reduction in nAChRs in Alzheimer's disease, the possibility exists that presynaptic nAChRs may be targets for A. To explore this possibility, we assessed the effect of A peptides on nicotine-evoked changes in presynaptic Ca²⁺ level via confocal imaging of isolated presynaptic nerve endings from rat hippocampus and neocortex. A_1-42 appeared to inhibit presynaptic nAChR activation by nicotine. Surprisingly, picomolar A_1-42 was found to directly evoke sustained increases in presynaptic Ca²⁺ via nAChRs, revealing that the apparent inhibitory action of A_1-42 was the result of an occlusion of nicotine to further stimulate the receptors. The direct effect of A was found to be sensitive to -bungarotoxin, mecamylamine, and dihydro--erythroidine, indicating involvement of 7-containing nAChRs and non-7-containing nAChRs. Prior depolarization strongly attenuated subsequent A-evoked responses in a manner dependent on the amplitude of the initial presynaptic Ca²⁺ increase, suggesting that nerve activity or Ca²⁺ channel density may control the impact of A on presynaptic nerve terminal function. Together, these results suggest that the sustained increases in presynaptic Ca²⁺ evoked by A may underlie disruptions in neuronal signaling via nAChRs in the early stages of Alzheimer's disease.

Key words: nicotinic receptor; amyloid; presynaptic; hippocampus; calcium imaging; Alzheimer's disease

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Received Feb. 13, 2003; revised May. 27, 2003; accepted May. 30, 2003.

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