Jay Amin1,2, Claire Paquet3,4,5, Alex Baker1,6, Ayodeji A Asuni7, Seth Love8, Clive Holmes1,2, Jacques Hugon3,4,5, James A R Nicoll1,6, Delphine Boche1. 1. Clinical Neurosciences, Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, UK. 2. Memory Assessment and Research Centre, Moorgreen Hospital, Southern Health Foundation Trust, Southampton, UK. 3. INSERM, U942, Paris, France. 4. Univ Paris Diderot, Sorbonne Paris Cité, UMRS 942, Paris, France. 5. Centre Mémoire de Ressources et de Recherche Paris Nord Ile de France, AP-HP, Hopital Lariboisière, Paris, France. 6. Department of Cellular Pathology, University Hospital Southampton NHS Foundation Trust, Southampton, UK. 7. Centre for Biological Sciences, Faculty of Natural and Environmental Science, University of Southampton, UK. 8. Department of Neuropathology, Institute of Clinical Neurosciences, School of Clinical Sciences, University of Bristol, Bristol, UK.
Abstract
AIMS: Active amyloid-β (Aβ) immunotherapy in Alzheimer's disease (AD) induces removal of Aβ and phosphorylated tau (ptau). Glycogen synthase kinase (GSK)-3β is a kinase, responsible for phosphorylation of tau, activation of which can be induced by phosphorylated double-stranded RNA-dependent protein kinase (pPKR). Using a post-mortem cohort of immunized AD cases, we investigated the effect of Aβ immunization on GSK-3β expression and pPKR. METHODS: We immunostained 11 immunized AD cases and 28 unimmunized AD cases for active, inactive and total GSK-3β, and for pPKR. Quantification of protein load was performed in the hippocampal region including CA1, subiculum and entorhinal cortex. RESULTS: All three areas showed a significant decrease in the three forms of GSK-3β (P < 0.05) and a nonsignificant trend towards lower pPKR load in the immunized AD cases compared with the unimmunized AD cases. CONCLUSION: The lower GSK-3β expression generated by Aβ immunotherapy shows evidence of a modification of the signalling pathway induced by GSK-3β leading to the overall reduction of tau, supporting the contention that in humans, GSK-3β unifies Aβ and tau-related neuropathology.
AIMS: Active amyloid-β (Aβ) immunotherapy in Alzheimer's disease (AD) induces removal of Aβ and phosphorylated tau (ptau). Glycogen synthase kinase (GSK)-3β is a kinase, responsible for phosphorylation of tau, activation of which can be induced by phosphorylated double-stranded RNA-dependent protein kinase (pPKR). Using a post-mortem cohort of immunized AD cases, we investigated the effect of Aβ immunization on GSK-3β expression and pPKR. METHODS: We immunostained 11 immunized AD cases and 28 unimmunized AD cases for active, inactive and total GSK-3β, and for pPKR. Quantification of protein load was performed in the hippocampal region including CA1, subiculum and entorhinal cortex. RESULTS: All three areas showed a significant decrease in the three forms of GSK-3β (P < 0.05) and a nonsignificant trend towards lower pPKR load in the immunized AD cases compared with the unimmunized AD cases. CONCLUSION: The lower GSK-3β expression generated by Aβ immunotherapy shows evidence of a modification of the signalling pathway induced by GSK-3β leading to the overall reduction of tau, supporting the contention that in humans, GSK-3β unifies Aβ and tau-related neuropathology.
Authors: James A R Nicoll; George R Buckland; Charlotte H Harrison; Anton Page; Scott Harris; Seth Love; James W Neal; Clive Holmes; Delphine Boche Journal: Brain Date: 2019-07-01 Impact factor: 13.501
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