Takata_2010_J.Biol.Chem_285_40180

Reference

Title : Galantamine-induced amyloid-{beta} clearance mediated via stimulation of microglial nicotinic acetylcholine receptors - Takata_2010_J.Biol.Chem_285_40180
Author(s) : Takata K , Kitamura Y , Saeki M , Terada M , Kagitani S , Kitamura R , Fujikawa Y , Maelicke A , Tomimoto H , Taniguchi T , Shimohama S
Ref : Journal of Biological Chemistry , 285 :40180 , 2010
Abstract :

Reduction of brain amyloid-beta (Abeta) has been proposed as a therapeutic target for Alzheimer disease (AD), and microglial Abeta phagocytosis is noted as an Abeta 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 Abeta deposits and expressed alpha7 nAChRs including the APL-binding site recognized with FK1 antibody. Treatment of rat microglia with galantamine significantly enhanced microglial Abeta phagocytosis, and acetylcholine competitive antagonists as well as FK1 antibody inhibited the enhancement. Thus, the galantamine-enhanced microglial Abeta phagocytosis required the combined actions of an acetylcholine competitive agonist and the APL for nAChRs. Indeed, depletion of choline, an acetylcholine-competitive alpha7 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 alpha7 nAChRs to choline and induces Ca(2+) influx into microglia. The Ca(2+)-induced intracellular signaling cascades may then stimulate Abeta phagocytosis through the actin reorganization. We further demonstrated that galantamine treatment facilitated Abeta 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.

PubMedSearch : Takata_2010_J.Biol.Chem_285_40180
PubMedID: 20947502

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Citations formats

Takata K, Kitamura Y, Saeki M, Terada M, Kagitani S, Kitamura R, Fujikawa Y, Maelicke A, Tomimoto H, Taniguchi T, Shimohama S (2010)
Galantamine-induced amyloid-{beta} clearance mediated via stimulation of microglial nicotinic acetylcholine receptors
Journal of Biological Chemistry 285 :40180

Takata K, Kitamura Y, Saeki M, Terada M, Kagitani S, Kitamura R, Fujikawa Y, Maelicke A, Tomimoto H, Taniguchi T, Shimohama S (2010)
Journal of Biological Chemistry 285 :40180