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

• DOI: 10.1523/jneurosci.23-17-06740.2003
• Publication Date: 2018-04-13T22:30:28Z
• Authors: John J. Dougherty; Jianlin Wu; Robert A. Nichols
• Keywords: 03 medical and health sciences; 0302 clinical medicine; 3. Good health

Alteration by β-amyloid (Aβ) 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 Aβ 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 Aβ. To explore this possibility, we assessed the effect of Aβ peptides on nicotine-evoked changes in presynaptic Ca2+level via confocal imaging of isolated presynaptic nerve endings from rat hippocampus and neocortex. Aβ1-42appeared to inhibit presynaptic nAChR activation by nicotine. Surprisingly, picomolar Aβ1-42was found to directly evoke sustained increases in presynaptic Ca2+via nAChRs, revealing that the apparent inhibitory action of Aβ1-42was the result of an occlusion of nicotine to further stimulate the receptors. The direct effect of Aβ was found to be sensitive to α-bungarotoxin, mecamylamine, and dihydro-β-erythroidine, indicating involvement of α7-containing nAChRs and non-α7-containing nAChRs. Prior depolarization strongly attenuated subsequent Aβ-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 Aβ on presynaptic nerve terminal function. Together, these results suggest that the sustained increases in presynaptic Ca2+evoked by Aβ may underlie disruptions in neuronal signaling via nAChRs in the early stages of Alzheimer's disease.