Donepezil modulates the endogenous immune response in Alzheimer’s disease, an ex vivo and in vitro study

Donepezil (DNPZ), an acetyl-cholinesterase inhibitor (AChEI), is widely used as a symptomatic drug in AD, given the involvement of cholinergic damage in the onset of memory loss. DNPZ, besides being able to improve acetylcholine (ACh) transmission, might have a neuroprotective effect reducing toxic Abeta fibrils and regulating the immune response. Considering that we previously showed a specific increase of plasma anti-Abeta1–42 antibodies in AD patients treated with AChEI, we evaluated in this study the role of DNPZ in favouring a Th2 phenotype, involved in modulating the immune humoral response. Moreover we hypothesized that this mechanism might be mediated by the a7-nicotinic ACh receptor expressed in lymphocytes. 60 patients with mild or moderate AD, either treated (n=22) or not (n=38) with DNPZ, and 30 controls were enrolled. AD DNPZ+ showed significantly higher plasma levels of anti-Abeta antibodies than DNPZ− (+40%) and lower levels of Abeta 1–42 than controls (−50%). In a subgroup of subjects, GATA-3, a transcription factor involved in Th2 differentiation, and a7nAChR expression was evaluated. No differences were found in GATA-3 mRNA in AD DNPZ+ when compared to DNPZ− and controls. On the opposite, we found by chromatine immunoprecipitation a significant three-fold increase of the association of GATA-3 with the IL-5-promoter in DNPZ+ patients, which also showed a significant twofold increase in a7-nAChR mRNA, with respect to DNPZ-ones. In vitro analyses demonstrated that the capacity of DNPZ to modulate GATA-3 expression is mediated by a7nAChR, since MLA, a specific antagonist, prevents it. Further studies are needed to better understand the role of DNPZ in modulating the immune response against Abeta, possibly ameliorating therapeutic strategies for AD