Lin_2020_Neurotherapeutics_17_676

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 (alpha7nAChRs) play an essential role in cognitive functions, binding with extracellular beta-amyloid (Abeta plaques) and inhibiting Abeta-induced neurotoxicity. alpha7nAChRs are impaired early in the course of AD; drugs targeting alpha7nAChRs are being hotly pursued as a treatment of AD. Encenicline, a partial selective agonist of alpha7nAChR 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 alpha7nAChRs 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 Abeta(1-42)-induced apoptosis by activating the JNK signaling pathway, thus enhancing alpha7nAChR expression, and also inhibits the Akt pathway, which further increases autophagosome biogenesis and autophagy. These effects can be reproduced by alpha7nAChR overexpression in the absence of galantamine. Importantly, the alpha7 subunit protein sequence of alpha7nAChRs contains 3 LC3-interacting regions; our immunoprecipitation data show that alpha7 binds with the autophagosomal marker protein LC3. This is the first report to provide evidence showing that the cell surface receptor alpha7nAChR acts as a cargo carrier for LC3 binding for Abeta(1-42) sequestration to autophagosomes, suggesting a novel mechanism for the neuroprotective efficacy of galantamine in AD.