1 3 Eur Arch Psychiatry Clin Neurosci DOI 10.1007/s00406-015-0600-6 ORIGINAL PAPER Increased iPLA2 activity and levels of phosphorylated GSK3B in platelets are associated with donepezil treatment in Alzheimer’s disease patients L. L. Talib 1 · S. R. Hototian 1 · H. P. G. Joaquim 1 · O. V. Forlenza 1 · W. F. Gattaz 1,2 Received: 24 December 2014 / Accepted: 15 April 2015 © Springer-Verlag Berlin Heidelberg 2015 After 6 months, we found an increase in phosphorylated GSK3B (p = 0.02). The present findings suggest two possi- ble mechanisms by which donepezil delays the progression of AD. The increment of iPLA2 activity may reduce the production of beta-amyloid plaques, whereas the phospho- rylation of GSK3B inactivates the enzyme, reducing thus the phosphorylation of tau protein. Keywords Alzheimer disease · Phospholipase A2 · Glycogen synthase kinase 3 · Platelets · Donepezil Introduction Pre-clinical and clinical studies suggest a neuroprotective role for acetylcholinesterase inhibitors (AChEI), which are widely used in the treatment of Alzheimer’s disease (AD) [1–3]. These drugs delay the progression of brain atrophy, indicating a disease modifying effect by attenuating neu- ronal death [4]. However, the protective mechanisms of donepezil have not yet been fully identified. Phospholipase A2 (PLA2) and glycogen synthase kinase 3B (GSK3B) are enzymes related to the neuropathological processes in AD and might constitute putative biomark- ers of the disease process since their measurement in the periphery seems to be related to their activity in the brain [5]. PLA2 PLA2 comprises a super-family of enzymes that have a major role in membrane phospholipid homeostasis. The activity of PLA2 generates intracellular signalling mol- ecules, and downstream products such as arachidonic acid and choline [6, 7]. PLA2 enzymes are classified into three Abstract Reduced phospholipase A2 (PLA2) activity and increased phosphorylation of glycogen synthase kinase 3B (GSK3B) participate in the production of beta-amyloid plaques and of neurofibrillary tangles, which are two neu- ropathological hallmarks of Alzheimer’s disease (AD). Experimental evidences suggest a neuroprotective effect of the cholinesterase inhibitor donepezil in the treatment the disease. The aims of the present study were to evaluate in AD patients the effects of treatment with donepezil on PLA2 activity and GSK3B level. Thirty patients with AD were treated during 6 months with 10 mg daily of done- pezil. Radio-enzymatic assays were used to measure PLA2 activity and Elisa assays for GSK3B level, both in platelets. Before treatment and after 3 and 6 months on donepezil, AD patients underwent a cognitive assessment and platelet samples were collected. Values were compared to a healthy control group of 42 sex- and age-matched elderly individu- als. Before treatment, iPLA2 activity was lower in patients with AD as compared to controls (p < 0.001). At base- line, no differences were found in GSK3B level between both groups. After 3 and 6 months of treatment, we found a significant increase in iPLA2 activity (p = 0.015 and p < 0.001, respectively). iPLA2 increment was related to the cognitive improvement during treatment (p = 0.037). * L. L. Talib ledatalib@gmail.com W. F. Gattaz gattaz@usp.br 1 Laboratory of Neuroscience (LIM-27), Department and Institute of Psychiatry, Faculty of Medicine, University of São Paulo, São Paulo, Brazil 2 Instituto de Psiquiatria, Hospital das Clínicas da Faculdade de Medicina da USP, Rua Dr. Ovídio Pires de Campos 785, São Paulo, SP 05403-010, Brazil