Galantamine Inhibits Aβ1-42-Induced Neurotoxicity by Enhancing α7nAChR Expression as a Cargo Carrier for LC3 Binding and Aβ1-42Engulfment During Autophagic Degradation

Despite Alzheimer's disease (AD) being the most common neurodegenerative disorder worldwide, no FDA-approved disease-modifying treatments have been approved for this condition since 2003. Neuronal-type alpha7 nicotinic acetylcholine receptors (alpha 7nAChRs) play an essential role in cognitive functions, binding with extracellular beta-amyloid (A beta plaques) and inhibiting A beta-induced neurotoxicity. alpha 7nAChRs are impaired early in the course of AD; drugs targeting alpha 7nAChRs are being hotly pursued as a treatment of AD. Encenicline, a partial selective agonist of alpha 7nAChR and modulator of acetylcholine, failed in phase III trials because of gastrointestinal side effects. We, therefore, evaluated the efficacy of galantamine, a positive allosteric modulator at alpha 7nAChRs and an acetylcholinesterase inhibitor, that has been used since 2000 as first-line treatment of mild-to-moderate dementia. This study highlights an important new benefit with galantamine. We found that galantamine inhibits A beta(1-42)-induced apoptosis by activating the JNK signaling pathway, thus enhancing alpha 7nAChR expression, and also inhibits the Akt pathway, which further increases autophagosome biogenesis and autophagy. These effects can be reproduced by alpha 7nAChR overexpression in the absence of galantamine. Importantly, the alpha 7 subunit protein sequence of alpha 7nAChRs contains 3 LC3-interacting regions; our immunoprecipitation data show that alpha 7 binds with the autophagosomal marker protein LC3. This is the first report to provide evidence showing that the cell surface receptor alpha 7nAChR acts as a cargo carrier for LC3 binding for A beta(1-42)sequestration to autophagosomes, suggesting a novel mechanism for the neuroprotective efficacy of galantamine in AD.