Co-activation of selective nicotinic acetylcholine receptors is required to reverse beta amyloid–induced Ca2+ hyperexcitation

Sun, Julianna L.; Stokoe, Sarah A.; Roberts, Jessica P.; Sathler, Matheus F.; Nip, Kaila; Shou, Jiayi; Ko, Kaitlyn; Tsunoda, Susan; Kim, Seonil

doi:10.1016/j.neurobiolaging.2019.09.005

Cited by 36 publications

(96 citation statements)

References 120 publications

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“…Both isomeric analogs of anabasine-isoanatabine and anatabine-have therapeutic potential and merit further investigation. It was recently reported that agonists that co-stimulate both of the major brain nAChRs have greater efficacy in protecting brain cells from β-amyloid [52]. Similarly, the precognitive effects of varenicline seem to depend on stimulation of both α4β2 and α7 nAChRs [53].…”

Section: Discussionmentioning

confidence: 99%

A Pharmacological Comparison of Two Isomeric Nicotinic Receptor Agonists: The Marine Toxin Isoanatabine and the Tobacco Alkaloid Anatabine

et al. 2020

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Many organisms possess "secondary" compounds to avoid consumption or to immobilize prey. While the most abundant or active compounds are initially investigated, more extensive analyses reveal other "minor" compounds with distinctive properties that may also be of biomedical and pharmaceutical significance. Here, we present an initial in vitro investigation of the actions of two isomeric tetrahydropyridyl ring-containing anabasine analogs: isoanatabine, an alkaloid isolated from a marine worm, and anatabine, a relatively abundant minor alkaloid in commercial tobacco plants. Both compounds have a double bond that is distal to the piperidine ring nitrogen of anabasine. Racemic isoanatabine and anatabine were synthesized and their S-and R-enantiomers were isolated by chiral high pressure liquid chromatography (HPLC). Both isoanatabines displayed higher efficacies at α4β2 nicotinic acetylcholine receptors (nAChRs) relative to the anatabines; R-isoanatabine was most potent. Radioligand binding experiments revealed similar α4β2 nAChR binding affinities for the isoanatabines, but R-anatabine affinity was twice that of S-anatabine. While the two anatabines and S-isoanatabine were highly efficacious agonists at α7 nAChRs, R-isoanatabine was only a weak partial agonist. The four compounds share an ability to stimulate both α4β2 and α7 nAChRs, a property that may be useful in developing more efficacious drugs to treat neurodegenerative and other medical disorders.

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Section: Discussionmentioning

confidence: 99%

A Pharmacological Comparison of Two Isomeric Nicotinic Receptor Agonists: The Marine Toxin Isoanatabine and the Tobacco Alkaloid Anatabine

et al. 2020

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“…Aβos increase Ca 2+ influx and cause intracellular Ca 2+ homeostasis dysregulation by binding to receptors on neuronal membranes and disrupting the structure and permeability of cell membranes [ 75 , 76 ]. Increased intracellular Ca 2+ induces the activization of the Ca 2+ /calmodulin-dependent phosphatase calcineurin (CaN) and glycogen synthase kinase 3β (GSK3β), which can induce hyperphosphorylation of tau, impair the transport of brain-derived neurotrophic factor (BDNF) and cause transport dysregulation in both axons and dendrites [ 77 ].…”

Section: The Neurotoxicological Mechanisms Of Aβosmentioning

confidence: 99%

The Toxicity and Polymorphism of β-Amyloid Oligomers

Huang

Liu

2020

IJMS

110

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It is widely accepted that β-amyloid oligomers (Aβos) play a key role in the progression of Alzheimer’s disease (AD) by inducing neuron damage and cognitive impairment, but Aβos are highly heterogeneous in their size, structure and cytotoxicity, making the corresponding studies tough to carry out. Nevertheless, a number of studies have recently made remarkable progress in the describing the characteristics and pathogenicity of Aβos. We here review the mechanisms by which Aβos exert their neuropathogenesis for AD progression, including receptor binding, cell membrane destruction, mitochondrial damage, Ca2+ homeostasis dysregulation and tau pathological induction. We also summarize the characteristics and pathogenicity such as the size, morphology and cytotoxicity of dimers, trimers, Aβ*56 and spherical oligomers, and suggest that Aβos may play a different role at different phases of AD pathogenesis, resulting in differential consequences on neuronal synaptotoxicity and survival. It is warranted to investigate the temporal sequence of Aβos in AD human brain and examine the relationship between different Aβos and cognitive impairment.

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“…Aβ has been reported to affect the function of the glutamatergic a-amino-3-hydroxy-5-methyl-4isoxazolepropionic acid receptors (AMPARs), which are important in synaptic plasticity (56). Several studies suggest Aβ-induced Ca 2+ hyperexcitation promotes AMPAR endocytosis, which ultimately decreases the surface expression of AMPA receptor subunits GluA1 and GluA2, a cellular mechanism underlying Aβ-induced depression of AMPAR-mediated synaptic transmission (32,(57)(58)(59)(60). Given that selective co-activation of α7-and α4β2-nAChRs reverses Ca 2+ hyperexcitation in cultured neurons (32), we examined whether selective co-activation of α7-and α4β2-nAChRs reversed the Aβ effects on surface expression of AMPARs.…”

Section: Selective Co-activation Of α7-and α4β2-nachrs Reverses Aβ-inmentioning

confidence: 99%

“…Several studies suggest Aβ-induced Ca 2+ hyperexcitation elevates activity of Ca 2+ -dependent phosphatase, calcineurin, which, in turn, will promote AMPAR endocytosis via dephosphorylation of AMPAR subunit GluA1 at serine 845, a residue that plays a crucial role in AMPAR surface expression during synaptic plasticity (32,57,58). In fact, previous studies reveal that Aβ reduces AMPAR GluA1 phosphorylation at serine 845 (pGluA1), which is strongly associated with disrupted LTP in AD (32,57,60). Consistently, hippocampal LTP can be blocked by either direct exogenous Aβ application at high levels or abnormally high levels of Aβ produced from AD transgenic mouse models (57,58,(61)(62)(63)(64).…”

Section: Selective Co-activation Of α7-and α4β2-nachrs Reverses Aβ-inmentioning

confidence: 99%

“…Thus, it is not surprising that these receptors modulators are only moderately effective (12,27,28). In addition, the observation that Aβ accumulates in brain regions enriched for α4β2-and α7-nAChRs may provide an important clue for the selective vulnerability of the hippocampus to Aβ toxicity given the high-affinity interaction between Aβ and these nAChRs (29)(30)(31)(32).…”

Section: Introductionmentioning

confidence: 99%

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Selective co-activation of α7- and α4β2-nicotinic acetylcholine receptors reverses beta-amyloid-induced synaptic dysfunction

Roberts

Stokoe

Sathler

et al. 2020

Preprint

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Beta-amyloid (Aβ) has been recognized as an early trigger in the pathogenesis of Alzheimers disease (AD) leading to synaptic and cognitive impairments. Aβ can alter neuronal signaling through interactions with nicotinic acetylcholine receptors (nAChRs), contributing to synaptic dysfunction in AD. The three major nAChR subtypes in the hippocampus are composed of α7-, α4β2-, and α3β4-nAChRs. A selectively affects α7- and α4β2-nAChRs, but not α3β4-nAChRs in hippocampal neurons, resulting inneuronal hyperexcitation. However, how nAChR subtype selectivity for Aβ affects synaptic function in AD is not completely understood. Here, we showed that Aβ associated with α7- and α4-containing nAChRs but not α3-containing receptors. Computational modeling suggested two amino acids in α7-nAChRs, Arginine 208 and Glutamate 211, were important for the interaction between Aβ and α7-containing nAChRs. These residues were found to be conserved only in the α7 and α4 subunits. We therefore mutated these amino acids in α7-containing nAChRs to mimic the α3 subunit and found that mutant α7-containing receptors were unable to interact with Aβ, providing direct molecular evidence for how Aβ selectively interacted with α7- and α4-containing receptors, but not α3-containing nAChRs. Selective co-activation of α7- and α4β2-nAChRs was also sufficient to reverse Aβ-induced AMPA receptor (AMPAR) dysfunction, including Aβ-induced reduction of AMPAR phosphorylation and surface expression in hippocampal neurons. Moreover, the Aβ-induced disruption of long-term potentiation was reversed by co-stimulation of α7- and α4β2-nAChRs. These findings support a novel mechanism for Aβ's impact on synaptic function in AD, namely the differential regulation of nAChR subtypes.

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Co-activation of selective nicotinic acetylcholine receptors is required to reverse beta amyloid–induced Ca2+ hyperexcitation

Cited by 36 publications

References 120 publications

A Pharmacological Comparison of Two Isomeric Nicotinic Receptor Agonists: The Marine Toxin Isoanatabine and the Tobacco Alkaloid Anatabine

A Pharmacological Comparison of Two Isomeric Nicotinic Receptor Agonists: The Marine Toxin Isoanatabine and the Tobacco Alkaloid Anatabine

The Toxicity and Polymorphism of β-Amyloid Oligomers

Selective co-activation of α7- and α4β2-nicotinic acetylcholine receptors reverses beta-amyloid-induced synaptic dysfunction

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