(I) Pharmacological profiling of a novel modulator of the α7 nicotinic receptor: Blockade of a toxic acetylcholinesterase-derived peptide increased in Alzheimer brains

Scheme of an intracellular cascade showing how AChE-peptide could instigate a feed-forward chain of pathological events. 1: AChE-peptide binds to α7 nicotinic receptor and enhances Ca2+ influx. Note that this action need not be restricted to cholinergic systems since ubiquitous dietary choline can act as an alternative primary ligand 2: Depolarisation activates voltage-sensitive calcium channels (L-VOCC). 3: Raised intracellular calcium induces increase in AChE G4 release. 4: Calcium triggers upregulation of the α7 nicotinic receptor causing more Ca2+ influx and generating still more targets for AChE-peptide. 5: Calcium activates enzyme GSK-3 that will (a) increase tau phosphorylation and AChE release and (b) activate γ-secretase/β-secretase thereby releasing Aβ to act at the NBP14-sensitive site on α7 nicotinic receptor, as shown by current data.206