Targeting alpha 7 nicotinic acetylcholine receptors and their protein interactions in Alzheimer's disease drug development

The decades-old cholinergic hypothesis of Alzheimer's disease (AD) led to clinical testing and FDA approval of acetylcholinesterase inhibitor drugs. Subsequently, the alpha 7 nicotinic acetylcholine receptor (alpha 7nAChR) was proposed as a new drug target for enhancing cholinergic neurotransmission. Nearly simultaneously, soluble amyloid beta(1-42) (A beta(42)) was shown to bind alpha 7nAChR with picomolar affinity to activate kinases that hyperphosphorylate tau, the precursor to tau-containing tangles. Multiple biopharmaceutical companies explored alpha 7nAChR as a drug target for AD, mostly to enhance neurotransmission. Directly targeting alpha 7nAChR proved to be a drug development challenge. The ultra-high-affinity interaction between A beta(42) and alpha 7nAChR posed a significant hurdle for direct competition in the AD brain. The receptor rapidly desensitizes, undermining efficacy of agonists. Drug discovery approaches therefore included partial agonists and allosteric modulators of alpha 7nAChR. After substantial effort, numerous drug candidates were abandoned due to lack of efficacy or drug-related toxicities. As alternatives, proteins interacting with alpha 7nAChR were sought. In 2016, a novel nAChR regulator was identified, but no drug candidates have emerged from this effort. In 2012, the interaction of filamin A with alpha 7nAChR was shown to be critical to A beta(42)'s toxic signaling via alpha 7nAChR, presenting a new drug target. The novel drug candidate simufilam disrupts the filamin A- alpha 7nAChR interaction, reduces A beta(42)'s high-affinity binding to alpha 7nAChR, and suppresses A beta(42)'s toxic signaling. Early clinical trials of simufilam showed improvements in experimental CSF biomarkers and indications of cognitive improvement in mild AD patients at 1 year. Simufilam is currently in phase 3 clinical trials as a disease-modifying treatment for AD.