Functional Interactions of Fibrillar and Oligomeric Amyloid-β with Alpha7 Nicotinic Receptors in Alzheimer's Disease

Abstract

Amyloid-β (Aβ) peptides in the brain of patients with Alzheimer's disease (AD) assemble into various aggregation forms that differ in size, structure, and functional properties. Previous studies have shown that Aβ binds to nicotinic acetylcholine receptors (nAChRs) and activates signaling cascades that result in the disruption of synaptic functions. These findings suggest a possible link between impaired cholinergic neurotransmitter function in AD and Aβ pathogenesis. However, it is not yet known how the different Aβ assemblies interact with specific nAChR subtypes. In the present study, we demonstrate that neurotoxicity in neuronal cells in culture induced by fibrillar Aβ(1-40) is prevented through an α7 nAChR-dependent mechanism. The α7 nAChR agonists varenicline and JN403 increased binding of the amyloid ligand [³H]PIB to fibrillar Aβ in AD frontal cortex autopsy tissue. This suggests that the presence of nAChR agonists may inhibit interaction of Aβ with α7 nAChRs and prevent the formation of Aβ/α7 nAChR complexes. This interaction was confirmed in binding assays with [¹²⁵I]Aβ(1-40) and α7 nAChRs in autopsy brain tissue homogenates from the frontal cortex. The functional effects of Aβ fibrils and oligomers on nAChRs were examined by measuring intracellular calcium ([Ca(2+)](i) levels. Oligomeric, but not fibrillar Aβ(1-40), increased [Ca(2+)](i) in neuronal cells, and this effect was attenuated by varenicline. Our findings demonstrate that fibrillar Aβ exerts neurotoxic effects mediated partly through a blockade of α7 nAChRs, whilst oligomeric Aβ may act as a ligand activating α7 nAChRs, thereby stimulating downstream signaling pathways.

Mild cognitive impairment: pathology and mechanisms

“…This finding is in agreement with a previous observation that α-bungarotoxin binding correlates positively with Aβ plaque density in AD brains [128], and may reflect up regulation of α7 nAChR mRNA in cortical-projecting cholinergic neurons in early AD [34]. These results support a role for α7 nAChR in the development of cortical Aβ pathology [117, 177] and potential functional interaction between α7nAChR and Aβ [89]. The role of α4β2 nAChRs in MCI and AD is somewhat more controversial.…”

3H-Deprenyl and 3H-PIB autoradiography show different laminar distributions of astroglia and fibrillar β-amyloid in Alzheimer brain

“…The α7 nAChRs expressed on astrocytes could, thus, influence the excitability of astrocytes and their ability to propagate Ca 2+ -mediated signaling mechanisms. The amount of soluble and/or non-soluble Aβ forms as well as their internal versus external localization [68] in different brain regions could also influence intermediate processes between α7 nAChRs, glia and neurons, as implicated by recent findings from our group [6,69]. …”

Basal Forebrain Cholinergic Circuits and Signaling in Cognition and Cognitive Decline

“…Third is the potential role of presynaptic α7* AChRs as sites for Abeta peptide binding and activation of increased glutamate release in circuits related to cognition (Hascup and Hascup, 2016; Koukouli and Maskos, 2015; Lilja et al, 2011). It should also be noted that until recently, Abeta was thought to only interact with α7 homo-pentameric nAChRs.…”