Donepezil Modulates The Endogenous Immune Response: Implications For Alzheimer'S Disease

ObjectiveDonepezil (DNPZ) is a drug commonly used for Alzheimer's disease (AD) that may favour a T helper 2 phenotype leading to increased naturally occurring auto-antibodies (NAb) against beta-amyloid (A). We hypothesized the involvement of the cholinergic receptors [7-nicotnic acetylcholine receptor (7nAChR)] expressed on peripheral blood mononuclear cells (PBMC).MethodsFifty patients with mild-to-moderate AD, DNPZ treated (DNPZ+, n=25) or not (DNPZ-, n=25), and 25 matched controls were enrolled and PBMC extracted for both in vitro cultures, and real-time polymerase chain reaction and chromatin immunoprecipitation assay. Plasma samples were also obtained for A and NAb determination.ResultsDonepezil increased in vitro the expression of the transcription factor GATA binding protein 3 (GATA3) through 7nAChR, because prevented by the specific antagonist methyllycaconitine. Ex vivo PBMC 7nAChR mRNA expression was increased in both AD groups, while GATA3 expression was not. A significant increase in the GATA3/interleukin 5 promoter association was found in DNPZ+ patients. Finally, DNPZ+ patients showed both significantly higher plasma levels of anti-A NAb with respect to DNPZ- patients and A 1-42 with respect to normal controls.ConclusionsDonepezil might modulate a T helper 2 bias via 7nAChR leading to increased expression of NAb. Further studies on the role of the modulation of the immune response against A may pave the way to innovative therapeutic strategies for AD. Copyright (c) 2016 John Wiley & Sons, Ltd.