Nicotine Prevents Synaptic Impairment Induced by Amyloid-β Oligomers Through α7-Nicotinic Acetylcholine Receptor Activation

Abstract

An emerging view on Alzheimer disease's (AD) pathogenesis considers amyloid-β (Aβ) oligomers as a key factor in synaptic impairment and rodent spatial memory decline. Alterations in the α7-nicotinic acetylcholine receptor (α7-nAChR) have been implicated in AD pathology. Herein, we report that nicotine, an unselective α7-nAChR agonist, protects from morphological and synaptic impairments induced by Aβ oligomers. Interestingly, nicotine prevents both early postsynaptic impairment and late presynaptic damage induced by Aβ oligomers through the α7-nAChR/phosphatidylinositol-3-kinase (PI3K) signaling pathway. On the other hand, a cross-talk between α7-nAChR and the Wnt/β-catenin signaling pathway was revealed by the following facts: (1) nicotine stabilizes β-catenin, in a concentration-dependent manner; (2) nicotine prevents Aβ-induced loss of β-catenin through the α7-nAChR; and (3) activation of canonical Wnt/β-catenin signaling induces α7-nAChR expression. Analysis of the α7-nAChR promoter indicates that this receptor is a new Wnt target gene. Taken together, these results demonstrate that nicotine prevents memory deficits and synaptic impairment induced by Aβ oligomers. In addition, nicotine improves memory in young APP/PS1 transgenic mice before extensive amyloid deposition and senile plaque development, and also in old mice where senile plaques have already formed. Activation of the α7-nAChR/PI3K signaling pathway and its cross-talk with the Wnt signaling pathway might well be therapeutic targets for potential AD treatments.

The α7 nicotinic acetylcholine receptor: A mediator of pathogenesis and therapeutic target in autism spectrum disorders and Down syndrome

“…Moreover, this protective effect of nicotine M a n u s c r i p t 47 was blocked by Į-BTX, consistent with its mediation by the Į 7 nAChR. Further, nicotine preserved pre-and postsynaptic contact that was disrupted by Aȕ oligomers, a protective effect that was blocked by Į-BTX [59]. Importantly, this Į 7 nAChR-mediated protective effect against the toxicity of Aȕ oligomers in cultured hippocampal neurons involved, at least in part, the PI3K/Akt signaling pathway because it could be blocked by wortmannin, an inhibitor of the PI3K/Akt signaling pathway.…”

“…Importantly, protective effects of nicotine (10 μM) against the toxic effects of a one hour incubation with oligomers of Aȕ 1-42 (5 μM) were shown in primary cultures of E18 rat hippocampal neurons [59]. Specifically, the Aȕ oligomers caused a significant reduction in the number of postsynaptic density protein-95 (PSD-95) clusters, a marker of the integrity of the postsynaptic architecture.…”

“…Increasingly, soluble Aȕ oligomers, as opposed to "insoluble, high molecular weight Aȕ fibrils," are thought to be early mediators of the pathogenesis of AD, especially with respect to their toxic consequences at nicotinic cholinergic synapses [59]; the contribution of soluble Aȕ oligomers to the synaptic failure in DS is also very likely in view of the overexpression of APP. Importantly, protective effects of nicotine (10 μM) against the toxic effects of a one hour incubation with oligomers of Aȕ 1-42 (5 μM) were shown in primary cultures of E18 rat hippocampal neurons [59].…”

Therapeutic Potential ofα7 Nicotinic Acetylcholine Receptors

“…For example, it was shown that intraventricular injection of Ab 1-42 inhibited the pressor response of the heart rate caused by choline infusion (Li and Buccafusco, 2004). Further agreement for an interaction between a7 nAChRs and Ab was obtained in studies relying on selective a7 nAChR agonists (Wang et al, 2010b;Chen et al, 2010;Inestrosa et al, 2013). A further complexity might reside in the structural differences between homomeric a7 and heteromeric a7b2 nAChRs, as shown by intracellular recording in brain slices and from nAChRs expressed in Xenopus oocytes .…”

Altered filamin A enables amyloid beta-induced tau hyperphosphorylation and neuroinflammation in Alzheimer’s disease

“…Evidence that soluble Aβ induces tau pathology has grown, with hyperphosphorylation as the primary pathological modification [18] . Extensive research has elucidated the role of the α7nAChR in the toxicity of soluble Aβ 42 and the consequent hyperphosphorylation of tau [19][20][21][22][23][24] . Soluble Aβ 42 in monomeric or oligomeric form binds and signals via α7nAChR [25][26][27][28] , essentially hijacking this receptor to abnormally activate various kinases [27,[29][30][31] to heighten tau phosphorylation.…”