Selective coactivation of α7- and α4β2-nicotinic acetylcholine receptors reverses beta-amyloid–induced synaptic dysfunction

Jessica P Roberts,Sarah A Stokoe,Matheus F Sathler,Robert A Nichols,Seonil Kim

doi:10.1016/j.jbc.2021.100402

Abstract

Beta-amyloid (Aβ) has been recognized as an early trigger in the pathogenesis of Alzheimer's 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. Aβ selectively affects α7- and α4β2-nAChRs, but not α3β4-nAChRs in hippocampal neurons, resulting in neuronal 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 α4β2-nAChRs but not α3β4-nAChRs. Computational modeling suggested that two amino acids in α7-nAChRs, arginine 208 and glutamate 211, were important for the interaction between Aβ and α7-containing nAChRs. These residues are 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. In addition, mutant α3-containing nAChRs mimicking the α7 subunit interact with Aβ. This provides direct molecular evidence for how Aβ selectively interacted with α7- and α4β2-nAChRs, but not α3β4-nAChRs. Selective coactivation of α7- and α4β2-nAChRs also sufficiently reversed Aβ-induced AMPA receptor dysfunction, including Aβ-induced reduction of AMPA receptor phosphorylation and surface expression in hippocampal neurons. Moreover, costimulation of α7- and α4β2-nAChRs reversed the Aβ-induced disruption of long-term potentiation. These findings support a novel mechanism for Aβ's impact on synaptic function in AD, namely, the differential regulation of nAChR subtypes.

Highlights

Alzheimer’s disease (AD) is the predominant cause of dementia in the elderly, which is characterized by two histopathological hallmarks, beta-amyloid peptide (Aβ)-containing senile plaques and hyperphosphorylated tau-based neurofibrillary tangles [1]
In contrast to the single mutations, we found that the double α3 mutant was able to interact with Aβ42 when α3-nicotinic acetylcholine receptor (nAChR)-I284 for arginine (I284R)/N287 for glutamate (N287E)-GFP and the β4 subunits were expressed in HEK293 cells (Fig. 2I)
Nicotinic receptors have emerged as potential targets for reversing cognitive deficits in AD [68], owing to their noted potent regulation by Aβ, but there remains a need to determine the roles of specific nAChR subtypes in AD

Summary

Introduction

Alzheimer’s disease (AD) is the predominant cause of dementia in the elderly, which is characterized by two histopathological hallmarks, beta-amyloid peptide (Aβ)-containing senile plaques and hyperphosphorylated tau-based neurofibrillary tangles [1]. These data suggest that Aβ42 can associate with the α4β2- and α7-containing receptors but is unable to interact with α3β4-nAChRs. Given that coincubation with the Aβcore peptide was sufficient to reverse the Aβ42 effects on neuronal activity (Fig. 1), we carried out co-IP experiments with the Aβcore peptide to determine whether it could displace the interaction between Aβ42 and the receptors.

Results

Conclusion