Reduction of brain amyloid-␤ (A␤) has been proposed as a therapeutic target for Alzheimer disease (AD), and microglial A␤ phagocytosis is noted as an A␤ 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 A␤ deposits and expressed ␣7 nAChRs including the APL-binding site recognized with FK1 antibody. Treatment of rat microglia with galantamine significantly enhanced microglial A␤ phagocytosis, and acetylcholine competitive antagonists as well as FK1 antibody inhibited the enhancement. Thus, the galantamineenhanced microglial A␤ phagocytosis required the combined actions of an acetylcholine competitive agonist and the APL for nAChRs. Indeed, depletion of choline, an acetylcholinecompetitive ␣7 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 ␣7 nAChRs to choline and induces Ca 2؉ influx into microglia. The Ca 2؉ -induced intracellular signaling cascades may then stimulate A␤ phagocytosis through the actin reorganization. We further demonstrated that galantamine treatment facilitated A␤ 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.

Immunization with amyloid-b (Ab) peptides, a therapeutic approach in Alzheimer's disease (AD), reduces brain Ab, and microglial Ab phagocytosis has been proposed as an Ab-lowering mechanism. We transplanted rat microglia into the rat lateral ventricle just after intra-hippocampal Ab injection, and then investigated the contribution of exogenous microglia to Ab clearance. Migration of exogenous microglia from the lateral ventricle to Ab plaque was detected by magnetic resonance imaging and histochemical analysis, and the clearance of Ab was increased by transplantation. These results suggest the possible usefulness of exogenous microglia to the therapeutic approach in AD.