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

Abstract

Alteration by beta-amyloid (Abeta) 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 Abeta 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 Abeta. To explore this possibility, we assessed the effect of Abeta peptides on nicotine-evoked changes in presynaptic Ca2+ level via confocal imaging of isolated presynaptic nerve endings from rat hippocampus and neocortex. Abeta1-42 appeared to inhibit presynaptic nAChR activation by nicotine. Surprisingly, picomolar Abeta1-42 was found to directly evoke sustained increases in presynaptic Ca2+ via nAChRs, revealing that the apparent inhibitory action of Abeta1-42 was the result of an occlusion of nicotine to further stimulate the receptors. The direct effect of Abeta was found to be sensitive to alpha-bungarotoxin, mecamylamine, and dihydro-beta-erythroidine, indicating involvement of alpha7-containing nAChRs and non-alpha7-containing nAChRs. Prior depolarization strongly attenuated subsequent Abeta-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 Abeta on presynaptic nerve terminal function. Together, these results suggest that the sustained increases in presynaptic Ca2+ evoked by Abeta may underlie disruptions in neuronal signaling via nAChRs in the early stages of Alzheimer's disease.

Role of Key Aromatic Residues in the Ligand-binding Domain of α7 Nicotinic Receptors in the Agonist Action of β-Amyloid

“…Moreover, lipid interaction with the M4 transmembrane domain of the nAChR regulates its channel kinetics (39), and an interaction between A␤ and the lipid microenvironment around the nAChR may, in turn, regulate the receptor. We therefore first constructed a chimeric receptor containing the ECD from the ␣7-nAChR and the transmembrane and intracellular domains from the 5-HT 3 receptor (13, 37, 38), a ligand-gated ion channel that is very closely related to nicotinic receptors but not activated by A␤ (13,16,21). The results using the chimeric receptor (␣7 V202-5HT3A ) showed that the ECD of the ␣7-nAChR mediates activation of the receptor by A␤.…”

“…To do so, we constructed a chimeric receptor by fusing the nAChR ECD together with the transmembrane and intracellular domains of the 5-HT 3 serotonin receptor (13,37,38), as the binding site in ␣7-nAChR for classical nicotinic agonists is located in the ECD, but A␤ may also influence ␣7-nAChR activity through an additional interaction with the plasma membrane (23), perhaps via lipid-interacting residues in the transmembrane domains (39). Moreover, it was shown previously that the 5-HT 3 receptor is unaffected by A␤ (13,16,21). The chimeric receptor is denoted by ␣7 V202-5HT3A , as valine (V) at position 202 of mouse ␣7-nAChR lies at the border between the extracellular and first transmembrane domain of the ␣7-nAChR (38).…”

“…Specifically, ␣7-nAChRs located on hippocampal glutamatergic terminals regulate presynaptic glutamate release (19), and ␣7-nAChRs may facilitate long-term potentiation (20). When applied to rodent hippocampal nerve terminals, pM to nM concentrations of A␤ induced increases in presynaptic calcium, which were largely dependent upon the presence of presynaptic nAChRs, as demonstrated in pharmacological studies and studies using receptor null mutants (21,22). Picomolar A␤ was also shown to positively modulate synaptic plasticity in the hippocampus via presynaptic ␣7-nAChRs (7), as measured by an increase in long-term potentiation.…”

SSR180711, a Novel Selective α7 Nicotinic Receptor Partial Agonist: (1) Binding and Functional Profile

“…The levels of a7 n-AChR proteins have been shown to be decreased in the brain of AD patients, a pathology characterized by severe memory impairments (Nordberg, 2001). In addition, a direct interaction of the b-amyloid peptide with a7 n-AChRs has also been described at native and recombinant rat a7 n-AChRs, leading to functional alteration of these receptors (Dineley et al, 2002;Grassi et al, 2003;Dougherty et al, 2003;Nordberg, 2001). It has been hypothesized that the attention and cognitive symptoms that are characteristic of schizophrenia and AD may involve a degeneration or a hypofunction of the cholinergic inputs, originating from the septum to the hippocampus (Grassi et al, 2003;Gray et al, 1996;Freedman et al, 2000).…”

Chronic Nicotine Alters Nicotinic Receptor-induced Presynaptic Ca2+ Responses in Isolated Nerve Terminals

“…The regulation of neurotransmitter release by presynaptic nAChRs is also Ca 2+ -dependent, involving Ca 2+ influx via the nAChR ion pore and/or voltage-gated ion channels (VGCCs) activated by nAChR-mediated depolarization [10]. Direct measurement of presynaptic [Ca 2+ ] i in individual brain nerve terminals, coupled with pharmacological assessment, has demonstrated substantial and relatively sustained Ca 2+ increases to acute application of nicotine, the nature of which depends upon the specific brain region [11][12][13]. The sustained nicotine-induced presynaptic Ca 2+ responses are consistent with the sustained nicotine-induced increases in spontaneous excitatory release observed in a variety of preparations [14][15][16][17][18].…”