Modified Snake α-Neurotoxin Averts β-Amyloid Binding to α7 Nicotinic Acetylcholine Receptor and Reverses Cognitive Deficits in Alzheimer's Disease Mice

Alzheimer's disease (AD) is the most common cause of senile dementia and one of the greatest medical, social, and economic challenges. According to a dominant theory, amyloid-beta (A beta) peptide is a key AD pathogenic factor. A beta-soluble species interfere with synaptic functions, aggregate gradually, form plaques, and trigger neurodegeneration. The AD-associated pathology affects numerous systems, though the substantial loss of cholinergic neurons and alpha 7 nicotinic receptors (alpha 7AChR) is critical for the gradual cognitive decline. A beta binds to alpha 7AChR under various experimental settings; nevertheless, the functional significance of this interaction is ambiguous. Whereas the capability of low A beta concentrations to activate alpha 7AChR is functionally beneficial, extensive brain exposure to high A beta concentrations diminishes alpha 7AChR activity, contributes to the cholinergic deficits that characterize AD. A beta and snake alpha-neurotoxins competitively bind to alpha 7AChR. Accordingly, we designed a chemically modified alpha-cobratoxin (mToxin) to inhibit the interaction between A beta and alpha 7AChR. Subsequently, we examined mToxin in a set of original in silico, in vitro, ex vivo experiments, and in a murine AD model. We report that mToxin reversibly inhibits alpha 7AChR, though it attenuates A beta-induced synaptic transmission abnormalities, and upregulates pathways supporting long-term potentiation and reducing apoptosis. Remarkably, mToxin demonstrates no toxicity in brain slices and mice. Moreover, its chronic intracerebroventricular administration improves memory in AD-model animals. Our results point to unique mToxin neuroprotective properties, which might be tailored for the treatment of AD. Our methodology bridges the gaps in understanding A beta-alpha 7AChR interaction and represents a promising direction for further investigations and clinical development.