Donepezil modulates the endogenous immune response: implications for Alzheimer's disease.
Donepezil (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 (Aβ). We hypothesized the involvement of the cholinergic receptors [α7-nicotnic acetylcholine receptor (α7nAChR)] expressed on peripheral blood mononuclear cells (PBMC).



Fifty 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 Aβ and NAb determination.



Donepezil increased in vitro the expression of the transcription factor GATA binding protein 3 (GATA3) through α7nAChR, because prevented by the specific antagonist methyllycaconitine. Ex vivo PBMC α7nAChR 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-Aβ NAb with respect to DNPZ- patients and Aβ 1-42 with respect to normal controls.



Donepezil might modulate a T helper 2 bias via α7nAChR leading to increased expression of NAb. Further studies on the role of the modulation of the immune response against Aβ may pave the way to innovative therapeutic strategies for AD. Copyright © 2016 John Wiley & Sons, Ltd.
Laboratory of Neurobiology, School of Medicine and Milan Center for Neuroscience, University of Milano-Bicocca, Monza, Italy.
Elisa
E
Conti
Laboratory of Neurobiology, School of Medicine and Milan Center for Neuroscience, University of Milano-Bicocca, Monza, Italy.|Neurology, San Gerardo Hospital, Monza, Italy.
Lucio
L
Tremolizzo
Laboratory of Neurobiology, School of Medicine and Milan Center for Neuroscience, University of Milano-Bicocca, Monza, Italy.
Marta Elena
ME
Santarone
Laboratory of Neurobiology, School of Medicine and Milan Center for Neuroscience, University of Milano-Bicocca, Monza, Italy.
Marco
M
Tironi
Laboratory of Neurobiology, School of Medicine and Milan Center for Neuroscience, University of Milano-Bicocca, Monza, Italy.
Isabella
I
Radice
Laboratory of Neurobiology, School of Medicine and Milan Center for Neuroscience, University of Milano-Bicocca, Monza, Italy.
Chiara Paola
CP
Zoia
Neurology, Manzoni Hospital, Lecco, Italy.
Angelo
A
Aliprandi
Neurology, Manzoni Hospital, Lecco, Italy.
Andrea
A
Salmaggi
Laboratory of Chemical and Clinical Analyses, Magenta Hospital, Italy.
Roberto
R
Dominici
Laboratory of Chemical and Clinical Analyses, San Gerardo Hospital, Monza, Italy.
Marco
M
Casati
Laboratory of Neurobiology, School of Medicine and Milan Center for Neuroscience, University of Milano-Bicocca, Monza, Italy.|Neurology, San Gerardo Hospital, Monza, Italy.
Ildebrando
I
Appollonio
Laboratory of Neurobiology, School of Medicine and Milan Center for Neuroscience, University of Milano-Bicocca, Monza, Italy.|Neurology, San Gerardo Hospital, Monza, Italy.
Carlo
C
Ferrarese
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000188:drug therapy / Q000276:immunology* / Q000378:metabolism; D002478:Cells, Cultured; D000077265:Donepezil; D005260:Female; D050990:GATA3 Transcription Factor / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D007111:Immunity, Cellular / Q000187:drug effects / Q000502:physiology*; D007189:Indans / Q000494:pharmacology / Q000627:therapeutic use*; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D018697:Nootropic Agents / Q000494:pharmacology / Q000627:therapeutic use; D010880:Piperidines / Q000494:pharmacology / Q000627:therapeutic use*; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000276:immunology* / Q000378:metabolism
D050990:GATA3 Transcription Factor; C494749:GATA3 protein, human; D007189:Indans; D018697:Nootropic Agents; D010880:Piperidines; D064569:alpha7 Nicotinic Acetylcholine Receptor; D000077265:Donepezil
Alzheimer's disease; GATA3; beta-amyloid; donepezil; nicotinic acetylcholine receptors; peripheral blood mononuclear cells