1. Tau phosphorylation by glycogen synthase kinase 3β modulates enzyme acetylcholinesterase expression
- Author
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Javier Sáez-Valero, Jordi Alom, María-Salud García-Ayllón, Teodoro del Ser, Maria‐Angeles Cortés‐Gómez, Jesús Avila, Esther Llorens‐Álvarez, Instituto de Salud Carlos III, Centro Investigación Biomédica en Red Enfermedades Neurodegenerativas (España), Generalitat Valenciana, and European Commission
- Subjects
0301 basic medicine ,Male ,Glycogen synthase kinase-3β ,Xenopus ,Retinoic acid ,Biochemistry ,chemistry.chemical_compound ,Mice ,0302 clinical medicine ,GSK-3 ,Pregnancy ,Cricetinae ,Phosphorylation ,Neurotransmitter ,Cells, Cultured ,Aged, 80 and over ,Molecular Basis of Disease ,Mice, Inbred ICR ,biology ,tau phosphorylation ,glycogen synthase kinase‐3β inhibitor ,acetylcholinesterase ,glycogen synthase kinase‐3β ,Middle Aged ,Alzheimer's disease ,Acetylcholinesterase ,Cerebrospinal fluid ,language ,Original Article ,Female ,Acetylcholine ,medicine.drug ,medicine.medical_specialty ,Aché ,tau Proteins ,Tau phosphorylation ,CHO Cells ,cerebrospinal fluid ,Gene Expression Regulation, Enzymologic ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,Cricetulus ,Alzheimer Disease ,Internal medicine ,Cell Line, Tumor ,medicine ,Animals ,Humans ,Glycogen synthase kinase-3β inhibitor ,Glycogen synthase ,Aged ,Glycogen Synthase Kinase 3 beta ,language.human_language ,030104 developmental biology ,Endocrinology ,chemistry ,biology.protein ,Cholinergic ,ORIGINAL ARTICLES ,030217 neurology & neurosurgery ,Biomarkers - Abstract
Early View: Online Version of Record before inclusion in an issue., In Alzheimer's disease (AD), the enzyme acetylcholinesterase (AChE) co‐localizes with hyperphosphorylated tau (P‐tau) within neurofibrillary tangles. Having demonstrated that AChE expression is increased in the transgenic mouse model of tau Tg‐VLW, here we examined whether modulating phosphorylated tau levels by over‐expressing wild‐type human tau and glycogen synthase kinase‐3β (GSK3β) influences AChE expression. In SH‐SY5Y neuroblastoma cells expressing higher levels of P‐tau, AChE activity and protein increased by (20% ± 2%) and (440% ± 150%), respectively. Western blots and qPCR assays showed that this increment mostly corresponded to the cholinergic ACHE‐T variant, for which the protein and transcript levels increased ~60% and ~23%, respectively. Moreover, in SH‐SY5Y cells differentiated into neurons by exposure to retinoic acid (10 µM), over‐expression of GSK3β and tau provokes an imbalance in cholinergic activity with a decrease in the neurotransmitter acetylcholine in the cell (45 ± 10%). Finally, we obtained cerebrospinal fluid (CSF) from AD patients enrolled on a clinical trial of tideglusib, an irreversible GSK3β inhibitor. In CSF of patients that received a placebo, there was an increase in AChE activity (35 ± 16%) respect to basal levels, probably because of their treatment with AChE inhibitors. However, this increase was not observed in tideglusib‐treated patients. Moreover, CSF levels of P‐tau at the beginning measured by commercially ELISA kits correlated with AChE activity. In conclusion, this study shows that P‐tau can modulate AChE expression and it suggests that AChE may possibly increase in the initial phases of AD., MACG is supported by a GVA-Predoctoral fellowship from Generalitat Valenciana, Spain. This study was funded by Instituto de Salud Carlos III (ISCIII), Fondo de Investigaciones Sanitaria (grants CP11/00067 and PI17/00261 to MSGA); co-financed by Fondo Europeo de Desarrollo Regional and through CIBERNED, ISCIII, Spain.
- Published
- 2022