Discoveries and future significance of research into amyloid-beta/α7-containing nicotinic acetylcholine receptor (nAChR) interactions. (May 2023)

• Record Type: Journal Article
• Authors: Whiteaker, Paul; George, Andrew A.
• Is Part Of: Pharmacological research. Volume 191(2023)
• Publication Date: 2023-05
• Subjects: 5-HI 5-hydroxyindole -- α-Bgt α-bungarotoxin -- Aβ amyloid-β -- AD Alzheimer's disease -- BFCN basal forebrain cholinergic neuron -- DHβE dihydro-β-erythroidine -- fAβ fibrillar amyloid-β -- FRET Förster/fluorescence resonance energy transfer -- HDB horizontal limb of the diagonal band -- mAChR muscarinic acetylcholine choline receptor -- MCI mild cognitive impairment -- MLA methyllycaconitine -- MSDB medial septum and ventral diagonal band -- nAChR nicotinic acetylcholine receptor -- NB nucleus basalis -- oAβ oligomeric amyloid-β -- PAM positive allosteric modulator; Nicotinic receptors -- Alzheimer's disease -- Memory -- Neuronal hyperexcitation -- Cholinergic neurons -- Oligomeric amyloid-beta; Pharmacology -- Periodicals; Pharmacology -- Periodicals; Research -- Periodicals; Médicaments -- Recherche -- Périodiques; Pharmacologie -- Périodiques; 615.105
• DOI: 10.1016/j.phrs.2023.106743
• Languages: English
• ISSNs: 1043-6618

Abstract

Abstract: Initiated by findings that Alzheimer's disease is associated with a profound loss of cholinergic markers in human brain, decades of studies have examined the interactions between specific subtypes of nicotinic acetylcholine receptors and amyloid-β [derived from the amyloid precursor protein (APP), which is cleaved to yield variable isoforms of amyloid-β]. We review the evolving understanding of amyloid-β's roles in Alzheimer's disease and pioneering studies that highlighted a role of nicotinic acetylcholine receptors in mediating important aspects of amyloid-β's effects. This review also surveys the current state of research into amyloid-β / nicotinic acetylcholine receptor interactions. The field has reached an exciting point in which common themes are emerging from the wide range of prior research and a range of accessible, relevant model systems are available to drive further progress. We highlight exciting new areas of inquiry and persistent challenges that need to be considered while conducting this research. Studies of amyloid-β and the nicotinic acetylcholine receptor populations that it interacts with provide opportunities for innovative basic and translational scientific breakthroughs related to nicotinic receptor biology, Alzheimer's disease, and cholinergic contributions to cognition more broadly. Graphical Abstract: Experimental considerations that need to be addressed when studying Aβ42 /α7 * -nAChR interactions. When using Aβ42 to study nAChR, there are several important considerations to keep in mind. One key consideration is the need for isoform consistency, as different isoforms (e.g. monomeric, oligomeric, or fibrillar) of the receptor can have distinct properties and functions. Additionally, the use of physiological concentrations of Aβ (e.g. picomolar to nanomolar) is important to ensure relevance to the in vitro or in vivo setting. Another important factor to consider is the molecular site of interaction between amyloid beta and the receptor. For example, differences in receptor stoichiometry (i.e. α7 vs. α7β2 nAChR) can impact the downstream effects on neuronal signaling and synaptic plasticity. It is also important to consider the circuit-level interactions involved in the potential presynaptic and postsynaptic modulation of nicotinic acetylcholine receptors by Aβ, as this can have implications for cognitive function. The experimental model used is another critical consideration, as different models can have unique advantages and limitations for studying this interaction. Finally, cognitive implications of Aβ modulation of nicotinic acetylcholine receptors should be considered, as these receptors are known to play important roles in cognitive processes such as attention, learning, and memory. ga1