Drug Discovery Opinion

A number of groups are developing nicotinic α-7 receptor agonists or partial agonists for the treatment of Alzheimer’s disease. It is believed that α-7 agonists may contribute to symptomatic treatment through cholinergic mechanisms and may also protect vulnerable neurons from the neurotoxic effects of β-amyloid peptides. Although α-7 agonists have shown positive effects on cognition in both animal models and Alzheimer’s disease patients, researchers at the Salk Institute have suggested that ‘Nicotinic Receptor May Help Trigger Alzheimer’s Disease’, and propose that nicotinic α-7 receptor antagonists may be a better target for the treatment of Alzheimer’s disease.

The team found that, whereas transgenic mice that overexpress a mutated form of human amyloid precursor protein (APP) perform poorly in learning and memory tests, mice that overexpress APP but also lack nicotinic α-7 receptors perform as well as wild type mice. β-Amyloid disrupts the function of nicotinic α-7 receptors and is believed to accumulate in neurons via high affinity binding to the receptors. Agonist stimulation of α-7 receptors could thus restore impaired or altered intracellular signalling caused by β-amyloid and, by desensitisation or competitive binding, could also prevent internalisation of β-amyloid. Although it is likely that α-7 receptor antagonists would also prevent internalisation of β-amyloid, there is currently little other information to support the development of antagonists, especially given the toxicities of known α-7 receptor antagonists such as α-bungarotoxin and methyllycaconitine.

The study is published in the Journal of Neuroscience.

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