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

Abstract

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 (α7nAChRs) play an essential role in cognitive functions, binding with extracellular β-amyloid (Aβ plaques) and inhibiting Aβ-induced neurotoxicity. α7nAChRs are impaired early in the course of AD; drugs targeting α7nAChRs are being hotly pursued as a treatment of AD. Encenicline, a partial selective agonist of α7nAChR 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 α7nAChRs 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 Aβ1-42-induced apoptosis by activating the JNK signaling pathway, thus enhancing α7nAChR expression, and also inhibits the Akt pathway, which further increases autophagosome biogenesis and autophagy. These effects can be reproduced by α7nAChR overexpression in the absence of galantamine. Importantly, the α7 subunit protein sequence of α7nAChRs contains 3 LC3-interacting regions; our immunoprecipitation data show that α7 binds with the autophagosomal marker protein LC3. This is the first report to provide evidence showing that the cell surface receptor α7nAChR acts as a cargo carrier for LC3 binding for Aβ1-42 sequestration to autophagosomes, suggesting a novel mechanism for the neuroprotective efficacy of galantamine in AD.

• Authors: Ming-Wei Lin, Yi-Hung Chen, Han-Ben Yang, Chi Chien Lin, Shih-Ya Hung
• Journal: Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics (Neurotherapeutics) Vol. 17 Issue 2 Pg. 676-689 (04 2020) ISSN: 1878-7479 [Electronic] United States
• PMID: 31823156 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Amyloid beta-Peptides
• Cholinesterase Inhibitors
• MAP1LC3A protein, human
• Microtubule-Associated Proteins
• Peptide Fragments
• alpha7 Nicotinic Acetylcholine Receptor
• amyloid beta-protein (1-42)
• Galantamine

Topics

• Amyloid beta-Peptides (toxicity)
• Autophagy (drug effects)
• Cell Line
• Cholinesterase Inhibitors (pharmacology)
• Galantamine (pharmacology)
• Humans
• Microtubule-Associated Proteins (metabolism)
• Neurons (metabolism)
• Peptide Fragments (toxicity)
• Protein Transport (drug effects)
• alpha7 Nicotinic Acetylcholine Receptor (metabolism)