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

Abstract

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.

Nicotinic Acetylcholine Receptor Alterations in Autism Spectrum Disorders – Biomarkers and Therapeutic Targets

“…In the second study, elevated plasma sAPPα was found in 60% of known autistic children (n = 25) compared to healthy age-matched controls (Bailey et al, 2008). Recent studies showed that galantamine allosterically modulates microglial nAChRs and increases microglial beta-amyloid (A) phagocytosis Takata et al, 2010). Collectively, these studies suggest that positive allosteric modulators of 42 nAChRs, when used by themselves or in conjunction with agonists, may be beneficial in correcting deficits in the functions of 42 nAChRs and thereby core deficits of ASD.…”

Molecular Approaches to the Treatment, Prophylaxis, and Diagnosis of Alzheimer’s Disease: Tangle Formation, Amyloid-β, and Microglia in Alzheimer’s Disease

“…We have recently provided new evidence that modulation of microglial α7 nicotinic acetylcholine receptors (nAChRs) by galantamine or stimulation of α7 nAChRs by nicotine enhances Aβ phagocytosis in primary cultured rat microglia (51). Galantamine sensitizes microglial α7 nAChRs to choline and nicotine by binding to the allosterically potentiating ligand-binding site on α7 nAChRs.…”

Alzheimer’s disease as an inflammatory disease

“…In this amyloidosis microglia could exert neuroprotective activity by degrading Aβ (55). In AD, these cells have a reduced capacity for Aβ clearance, which results in additional accumulation of this peptide (56).…”