Cited by 177Alzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration MechanismsNicotinic Acetylcholine Receptors Study

Galantamine-induced Amyloid-β Clearance Mediated via Stimulation of Microglial Nicotinic Acetylcholine Receptors

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Takata, Kazuyuki, Kitamura, Yoshihisa, Saeki, Mana, Terada, Maki, Kagitani, Sachiko, Kitamura, Risa, Fujikawa, Yasuhiro, Maelicke, Alfred +3 more·2010·Journal of Biological Chemistry

Abstract

Reduction of brain amyloid-β (Aβ) has been proposed as a therapeutic target for Alzheimer disease (AD), and microglial Aβ phagocytosis is noted as an Aβ clearance system in brains. Galantamine is an acetylcholinesterase inhibitor approved for symptomatic treatment of AD. Galantamine also acts as an allosterically potentiating ligand (APL) for nicotinic acetylcholine receptors (nAChRs). APL-binding site is located close to but distinct from that for acetylcholine on nAChRs, and FK1 antibody specifically binds to the APL-binding site without interfering with the acetylcholine-binding site. We found that in human AD brain, microglia accumulated on Aβ deposits and expressed α7 nAChRs including the APL-binding site recognized with FK1 antibody. Treatment of rat microglia with galantamine significantly enhanced microglial Aβ phagocytosis, and acetylcholine competitive antagonists as well as FK1 antibody inhibited the enhancement. Thus, the galantamine-enhanced microglial Aβ phagocytosis required the combined actions of an acetylcholine competitive agonist and the APL for nAChRs. Indeed, depletion of choline, an acetylcholine-competitive α7 nAChR agonist, from the culture medium impeded the enhancement. Similarly, Ca(2+) depletion or inhibition of the calmodulin-dependent pathways for the actin reorganization abolished the enhancement. These results suggest that galantamine sensitizes microglial α7 nAChRs to choline and induces Ca(2+) influx into microglia. The Ca(2+)-induced intracellular signaling cascades may then stimulate Aβ phagocytosis through the actin reorganization. We further demonstrated that galantamine treatment facilitated Aβ clearance in brains of rodent AD models. In conclusion, we propose a further advantage of galantamine in clinical AD treatment and microglial nAChRs as a new therapeutic target.

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  1. Janus, C., Pearson, J., McLaurin, J., Mathews, P. M., Jiang, Y., Schmidt, S. D., Chishti, M. A., Horne, P., Heslin, D., French, J., Mount, H. T., Nixon, R. A., Mercken, M., Bergeron, C., Fraser, P. E., St George-Hyslop, P., and Westaway, D. (2000) Nature 408, 979 -982
  2. Okamoto, K., Narayanan, R., Lee, S. H., Murata, K., and Hayashi, Y. (2007) Proc. Natl. Acad. Sci. U.S.A. 104, 6418 -6423

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Authors
Takata, K., Kitamura, Y., Saeki, M., Terada, M., Kagitani, S., Kitamura, R., Fujikawa, Y., Maelicke, A., Tomimoto, H., Taniguchi, T., & Shimohama, S.
Affiliations
  • Kyoto Pharmaceutical University (JP)
  • Mie University (JP)
  • Sapporo Medical University (JP)
Corresponding author
  • Kitamura, Yoshihisa
  • Shimohama, Shun
Venue
Journal of Biological Chemistry
Publisher
Elsevier BV
Published
2010-12
Volume
285
Issue
51
Pages
40180-40191
ISSN
0021-9258 (ISSN-L)
OpenAlex
W2022036412
Cited by
176
References
60
Citations by year
2026: 7 · 2025: 11 · 2024: 7 · 2023: 11 · 2022: 10 · 2021: 12 · 2020: 16 · 2019: 13 · 2018: 11 · 2017: 13 · 2016: 16 · 2015: 16 · 2014: 8 · 2013: 12 · 2012: 6
FWCI
5.20
Type
journal article
Language
en
Open access
Locations
  • Journal of Biological Chemistry (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nicotinic Acetylcholine Receptors Study
Keywords
galantamine, amyloid-beta clearance, microglia, alpha7 nicotinic acetylcholine receptor, choline, calcium influx, actin reorganization, calmodulin signaling, Alzheimer's disease, microglial phagocytosis
MeSH terms
Aged, Alzheimer Disease, Animals, Antibodies, Monoclonal, Binding Sites, Calmodulin, Cells, Cultured, Choline, Cholinesterase Inhibitors, Disease Models, Animal, Female, Galantamine, Hippocampus, Humans, Male, Phagocytosis, Receptors, Nicotinic, Amyloid beta-Peptides, Rats, Wistar, Microglia, Nootropic Agents, Calcium Signaling, Rats

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