Imipramine and citalopram facilitate amyloid precursor protein secretion in vitro.
Comorbid depression of Alzheimer's disease (AD) is a common mood disorder in the elderly and a broad spectrum of antidepressants have been used for its treatment. Abeta peptides and other derivatives of the amyloid precursor protein (APP) have been implicated as central to the pathogenesis of AD. However, the functional relationship of APP and its proteolytic derivatives to antidepressant therapy is not known. In this study, Western blotting was used to test the ability of the tricyclic antidepressant (TCA) imipramine or the selective serotonin reuptake inhibitor (SSRI) citalopram to change the release of APP and the protein kinase C (PKC) content. Both antidepressants increased APP secretion in primary rat neuronal cultures. Imipramine or citalopram enhanced the level of secreted APP by 3.2- or 3.4-fold, respectively. Increases in PKC level were observed only after imipramine treatment. These in vitro data suggest that both TCA and SSRI are able to interfere with the APP metabolism. Imipramine promotes the non-amyloidogenic route of APP processing via stimulatory effects on PKC. We propose that PKC is not involved in the mechanism underlying the effects of citalopram on the APP metabolism. Since the secreted APP is not further available for the pathological cleavage of beta- and gamma-secretases, antidepressant medication might be beneficial in AD therapy.
Pákáski
Magdolna
M
Alzheimer's Disease Research Centre, Department of Psychiatry, University of Szeged, Semmelweis 6, H-6725 Szeged, Hungary. pakaski@comser.szote-u.szeged.hu
Bjelik
Annamária
A
Hugyecz
Marietta
M
Kása
Péter
P
Janka
Zoltán
Z
Kálmán
János
J
D000544:Alzheimer Disease / Q000150:complications / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D000929:Antidepressive Agents, Tricyclic / Q000494:pharmacology; D020532:Basal Nucleus of Meynert / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D015283:Citalopram / Q000494:pharmacology*; D017077:Culture Media, Conditioned / Q000737:chemistry; D003866:Depressive Disorder / Q000150:complications / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D007099:Imipramine / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism*; D011493:Protein Kinase C / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D000929:Antidepressive Agents, Tricyclic; D015283:Citalopram; D017077:Culture Media, Conditioned; D007099:Imipramine; D011493:Protein Kinase C; D017367:Selective Serotonin Reuptake Inhibitors