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

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.

Keywords: Alzheimer’s disease; Cholinergic neurons; Memory; Neuronal hyperexcitation; Nicotinic receptors; Oligomeric amyloid-beta.

Fig. 1.

Oligomeric amyloid-β (oAb₄₂) interactions and α7*-nAChR. (A) Under neuronormal conditions, both homomeric α7- and heteromeric α7β2-nAChRs are activated by the endogenous ligand acetylcholine (ACh; yellow circle). Homomeric α7-only nAChR harbor competitive agonist binding pockets at the interfaces between “principal” (+) faces of each α7 subunit and the opposing “complementary” faces (−) provided by adjacent α7 subunits. Heteromeric α7β2-nAChRs host competitive agonist binding pockets only at the interfaces between adjacent α7 subunit interfaces. (B) During periods of elevated oAb₄₂, oAb₄₂ binds to and activates both α7-only- and α7β2-nAChR subtypes. However, as described in [41] oAβ₄₂ selectively enhances the single-channel open-dwell times of α7β2-containing nAChRs. The location(s) through which oAβ produce α7*-nAChR activation are not yet defined (as indicated by a question mark, although there is evidence for a non-competitive / allosteric mode of action (please see text).

Fig. 2.

Local excitatory and inhibitory cellular processes that mediate basal forebrain cholinergic (BFCN) excitability. Within the medial septum, glutamatergic (light blue) and GABAergic (yellow) inputs regulate BFCN (green) excitability through α7*-nAChR-mediated synaptic transmission. Given the potential expression of α7*-nAChR (α7-only and/or (α7β2-nAChR; indicated by green and red cylinders, respectively) on glutamatergic and GABAergic terminals, the observed Aβ-induced BFCN hyperexcitability [41] may occur through enhanced glutamatergic synaptic transmission directly onto BFCNs or through disinhibition of GABAergic transmission onto BFCNs (i.e., circuit-based effects) In addition, oAβ₄₂/α7*-nAChR interactions directly on BFCNs produce enhanced BFCN excitability. We have shown that BFCN hyperexcitation occurs through alterations in the intrinsic properties of BFCNs [likely via alterations in function of Ca²⁺ mediated or voltage-dependent potassium (K⁺) channels; blue triangles] [41].