Abstract
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-β (Aβ) peptide is a key AD pathogenic factor. Aβ-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 α7 nicotinic receptors (α7AChR) is critical for the gradual cognitive decline. Aβ binds to α7AChR under various experimental settings; nevertheless, the functional significance of this interaction is ambiguous. Whereas the capability of low Aβ concentrations to activate α7AChR is functionally beneficial, extensive brain exposure to high Aβ concentrations diminishes α7AChR activity, contributes to the cholinergic deficits that characterize AD. Aβ and snake α-neurotoxins competitively bind to α7AChR. Accordingly, we designed a chemically modified α-cobratoxin (mToxin) to inhibit the interaction between Aβ and α7AChR. 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 α7AChR, though it attenuates Aβ-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 Aβ-α7AChR interaction and represents a promising direction for further investigations and clinical development.
Highlights
Alzheimer’s disease (AD) is a severe neurodegenerative disorder characterized by the gradual accumulation of misfolded proteins and their fragments in the brain, progressive neuronal loss, and neuroinflammation, followed by the steady and inevitable decline in memory and other cognitive functions [1]
Initial preclinical studies with cholinomimetic agents, and physostigmine in particular, in monkeys [4] have been followed by numerous clinical trials, which eventually resulted in the approval by the Food and Drug Administration (FDA) of Tacrine as the very first drug targeting memory and thinking problems associated with AD
We hypothesize that the modified toxin is capable of preventing some of the deleterious effects of Aβ in the brain, which we examine in a series of in vitro, ex vivo, and in vivo experiments
Summary
Alzheimer’s disease (AD) is a severe neurodegenerative disorder characterized by the gradual accumulation of misfolded proteins and their fragments in the brain, progressive neuronal loss, and neuroinflammation, followed by the steady and inevitable decline in memory and other cognitive functions [1]. The cholinergic hypothesis of AD, introduced some 40 years ago, suggests that a dysfunction of cholinergic neurons in the brain contributes to the cognitive decline. Mounting clinical and experimental evidence has proven the role of cholinergic dysfunction in the development of AD-associated cognitive decline, and offered a promising treatment approach. Initial preclinical studies with cholinomimetic agents, and physostigmine in particular, in monkeys [4] have been followed by numerous clinical trials, which eventually resulted in the approval by the Food and Drug Administration (FDA) of Tacrine as the very first drug targeting memory and thinking problems associated with AD. Inhibitors of acetylcholinesterase decrease the rate of acetylcholine (ACh) breakdown and improve cholinergic neurotransmission, even though their efficacy is noticeably limited [6]
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