Molecular Modulation of Human α7 Nicotinic Receptor by Amyloid-β Peptides

Abstract

Amyloid β peptide (Aβ) is a key player in the development of Alzheimer’s disease (AD). It is the primary component of senile plaques in AD patients and is also found in soluble forms. Cholinergic activity mediated by α7 nicotinic receptors has been shown to be affected by Aβ soluble forms. To shed light into the molecular mechanism of this effect, we explored the direct actions of oligomeric Aβ1–40 and Aβ1–42 on human α7 by fluorescence spectroscopy and single-channel recordings. Fluorescence measurements using the conformational sensitive probe crystal violet (CrV) revealed that in the presence of Aβ α7 undergoes concentration-dependent conformational changes. Exposure of α7 to 100 pM Aβ changes CrV KD towards that of the desensitized state. However, α7 is still reactive to high carbamylcholine (Carb) concentrations. These observations are compatible with the induction of active/desensitized states as well as of a novel conformational state in the presence of both Aβ and Carb. At 100 nM Aβ, α7 adopts a resting-state-like structure which does not respond to Carb, suggesting stabilization of α7 in a blocked state. In real time, we found that Aβ is capable of eliciting α7 channel activity either in the absence or presence of the positive allosteric modulator (PAM) PNU-120596. Activation by Aβ is favored at picomolar or low nanomolar concentrations and is not detected at micromolar concentrations. At high Aβ concentrations, the mean duration of activation episodes elicited by ACh in the presence of PNU-120596 is significantly reduced, an effect compatible with slow open-channel block. We conclude that Aβ directly affects α7 function by acting as an agonist and a negative modulator. Whereas the capability of low concentrations of Aβ to activate α7 could be beneficial, the reduced α7 activity in the presence of higher Aβ concentrations or its long exposure may contribute to the cholinergic signaling deficit and may be involved in the initiation and development of AD.

Cholinergic-like neurons carrying PSEN1 E280A mutation from familial Alzheimer’s disease reveal intraneuronal sAPPβ fragments accumulation, hyperphosphorylation of TAU, oxidative stress, apoptosis and Ca2+ dysregulation: Therapeutic implications

“…We found that the PSEN1 E280A ChLN response to ACh was significantly reduced by day 4 post transdifferentiation. Notably, Aβ has been shown to directly affect α7 nicotinic ACh receptor (α7 nAChR) function by acting as an agonist (~100 nM) and a negative modulator (at high concentrations) [71]. Consistent with this view, we confirmed that PSEN1 E280A ChLNs secreted aberrant amounts of Aβ42 (e.g.,~2500-f.i.)…”

Cholinergic-like neurons carrying PSEN1 E280A mutation from familial Alzheimer’s disease reveal intraneuronal Aβ42 peptide accumulation, hyperphosphorylation of TAU, oxidative stress, apoptosis and Ca2+ flux dysregulation: Therapeutic Implications

“…We found that the PSEN1 E280A ChLN response to ACh was significantly reduced by day 4 post transdifferentiation. Notably, A has been shown to directly affect 7 nicotinic ACh receptor (7 nAChR) function by acting as an agonist (~100 nM) and a negative modulator (at high concentrations) [71]. Consistent with this view, we confirmed that PSEN1 E280A…”

Neuromodulatory Action of Picomolar Extracellular Aβ42 Oligomers on Presynaptic and Postsynaptic Mechanisms Underlying Synaptic Function and Memory

“…Consistently, A␤ binds different targets in a concentration-dependent manner (Mura et al, 2012;Zappettini et al, 2012). and, recently, it has been shown that A␤ directly affects ␣7-nAchR conformation and function by acting as an agonist when at picomolar concentrations or as an antagonist when at nanomolar concentrations (Lasala et al, 2019). It should be also considered that at high A␤ concentrations, the amount of oligomerization proportionally increases overrunning the physiological level (Gulisano et al, 2018a,b).…”