Nicotinic Acetylcholine Receptor Agonists for the Treatment of Alzheimer’s Dementia: An Update

Hoskin, Justin L.; Al-Hasan, Yazan; Sabbagh, Marwan N.

doi:10.1093/ntr/nty116

Cited by 89 publications

(81 citation statements)

References 93 publications

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“…Nonetheless, nAChR agonists have consistently suggested promising approaches in the treatment of AD (77). However, clinical trials thus far have been challenged by adverse effects or minimal improvement (78). In particular, stimulating only one type of nAChRs by using a subtype-specific agonist was found to either enhance cognitive performance or have no beneficial effect.…”

Section: Discussionmentioning

confidence: 99%

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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Section: Discussionmentioning

confidence: 99%

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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“…In this context, the α7 and α4β2 subtypes located mainly in the central nervous system (CNS) have been initially exploited as drug targets in the discovery of drugs for neurodegenerative diseases [ 5 , 6 , 7 ]. For example, compounds acting on α7 and α4β2 nAChRs have been developed as drugs for neuropsychiatric disorders such as Alzheimer′s disease, schizophrenia, Parkinson’s disease, and autism [ 8 , 9 ]. Nowadays, α3β4 nAChR has emerged as an attractive therapeutic target for drug addiction as evidenced by its high expression in specific brain regions associated with addiction and reward systems e.g., medial habenula (MHb), interpeduncular nucleus (IPN), and pineal gland [ 10 ].…”

Section: Introductionmentioning

confidence: 99%

In Silico Finding of Key Interaction Mediated α3β4 and α7 Nicotinic Acetylcholine Receptor Ligand Selectivity of Quinuclidine-Triazole Chemotype

Arunrungvichian

Chongruchiroj

Schüürmann

et al. 2020

IJMS

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The selective binding of six (S)-quinuclidine-triazoles and their (R)-enantiomers to nicotinic acetylcholine receptor (nAChR) subtypes α3β4 and α7, respectively, were analyzed by in silico docking to provide the insight into the molecular basis for the observed stereospecific subtype discrimination. Homology modeling followed by molecular docking and molecular dynamics (MD) simulations revealed that unique amino acid residues in the complementary subunits of the nAChR subtypes are involved in subtype-specific selectivity profiles. In the complementary β4-subunit of the α3β4 nAChR binding pocket, non-conserved AspB173 through a salt bridge was found to be the key determinant for the α3β4 selectivity of the quinuclidine-triazole chemotype, explaining the 47–327-fold affinity of the (S)-enantiomers as compared to their (R)-enantiomer counterparts. Regarding the α7 nAChR subtype, the amino acids promoting a however significantly lower preference for the (R)-enantiomers were the conserved TyrA93, TrpA149 and TrpB55 residues. The non-conserved amino acid residue in the complementary subunit of nAChR subtypes appeared to play a significant role for the nAChR subtype-selective binding, particularly at the heteropentameric subtype, whereas the conserved amino acid residues in both principal and complementary subunits are essential for ligand potency and efficacy.

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“…Future research is needed to elucidate how this interaction is changing in different individuals at different stages of AD and what is the cellular mechanism involved to come up with better therapeutic approaches for AD treatment. The review by Hoskin et al, 2019, summarizes some of the mechanisms of action of some studied drugs that target the nAchRs in AD and the observed effects [ 45 ].…”

Section: Acetylcholine Cholinergic System and Alzheimer’s Diseasementioning

confidence: 99%

The Cholinergic System, the Adrenergic System and the Neuropathology of Alzheimer’s Disease

Bekdash

2021

IJMS

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Neurodegenerative diseases are a major public health problem worldwide with a wide spectrum of symptoms and physiological effects. It has been long reported that the dysregulation of the cholinergic system and the adrenergic system are linked to the etiology of Alzheimer’s disease. Cholinergic neurons are widely distributed in brain regions that play a role in cognitive functions and normal cholinergic signaling related to learning and memory is dependent on acetylcholine. The Locus Coeruleus norepinephrine (LC-NE) is the main noradrenergic nucleus that projects and supplies norepinephrine to different brain regions. Norepinephrine has been shown to be neuroprotective against neurodegeneration and plays a role in behavior and cognition. Cholinergic and adrenergic signaling are dysregulated in Alzheimer’s disease. The degeneration of cholinergic neurons in nucleus basalis of Meynert in the basal forebrain and the degeneration of LC-NE neurons were reported in Alzheimer’s disease. The aim of this review is to describe current literature on the role of the cholinergic system and the adrenergic system (LC-NE) in the pathology of Alzheimer’s disease and potential therapeutic implications.

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Nicotinic Acetylcholine Receptor Agonists for the Treatment of Alzheimer’s Dementia: An Update

Cited by 89 publications

References 93 publications

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

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

In Silico Finding of Key Interaction Mediated α3β4 and α7 Nicotinic Acetylcholine Receptor Ligand Selectivity of Quinuclidine-Triazole Chemotype

The Cholinergic System, the Adrenergic System and the Neuropathology of Alzheimer’s Disease

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