Tau phosphorylation by glycogen synthase kinase 3ß modulates enzyme acetylcholinesterase expression.
Por:
Cortés-Gómez MÁ, Llorens-Álvarez E, Alom J, Del Ser T, Avila J, Sáez-Valero J and García-Ayllón MS
Publicada:
1 jun 2021
Ahead of Print:
21 sep 2020
Resumen:
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-3ß (GSK3ß) 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 GSK3ß 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 GSK3ß 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.
Filiaciones:
Cortés-Gómez MÁ:
Hospital General Universitario de Elche, FISABIO, Unidad de Investigación, Elche, Spain
Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain
Instituto de Neurociencias de Alicante, Universidad Miguel Hernández-CSIC, Sant Joan d'Alacant, Spain
Llorens-Álvarez E:
Hospital General Universitario de Elche, FISABIO, Unidad de Investigación, Elche, Spain
Instituto de Neurociencias de Alicante, Universidad Miguel Hernández-CSIC, Sant Joan d'Alacant, Spain
Alom J:
Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain
Servicio de Neurología, Hospital General Universitario de Elche, FISABIO, Elche, Spain
Del Ser T:
Alzheimer's Disease Investigation Research Unit, CIEN Foundation, Queen Sofia Foundation Alzheimer Research Center, Madrid, Spain
Avila J:
Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain
Department of Molecular Neuropathology, Centro de Biología Molecular 'Severo Ochoa', CBMSO, CSIC-UAM, Madrid, Spain
:
Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain
Instituto de Neurociencias de Alicante, Universidad Miguel Hernández-CSIC, Sant Joan d'Alacant, Spain
García-Ayllón MS:
Hospital General Universitario de Elche, FISABIO, Unidad de Investigación, Elche, Spain
Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain
Instituto de Neurociencias de Alicante, Universidad Miguel Hernández-CSIC, Sant Joan d'Alacant, Spain
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