UvA-DARE (Digital Academic Repository) Let’s not forget: Peptidases in Alzheimer’s disease Stargardt, A. Publication date 2014 Document Version Final published version Link to publication Citation for published version (APA): Stargardt, A. (2014). Let’s not forget: Peptidases in Alzheimer’s disease. [Thesis, fully internal, Universiteit van Amsterdam]. General rights It is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), other than for strictly personal, individual use, unless the work is under an open content license (like Creative Commons). Disclaimer/Complaints regulations If you believe that digital publication of certain material infringes any of your rights or (privacy) interests, please let the Library know, stating your reasons. In case of a legitimate complaint, the Library will make the material inaccessible and/or remove it from the website. Please Ask the Library: https://uba.uva.nl/en/contact, or a letter to: Library of the University of Amsterdam, Secretariat, Singel 425, 1012 WP Amsterdam, The Netherlands. You will be contacted as soon as possible. UvA-DARE is a service provided by the library of the University of Amsterdam (https://dare.uva.nl) Download date:18 Feb 2023 LET’S NOT FORGET L E T Peptidases in Alzheimer’s Disease ’S N O T F O R G E T P e p t id a s e s in A l z h e im e r ’s D is e a s e - A n it a S t a r g a r d t Peptidases in Alzheimer’s Disease Anita Stargardt LET’S NOT FORGET PEPTIDASES IN ALZHEIMER’S DISEASE Anita Stargardt ISBN/EAN: 978-94-6108-842-0 The research described in this thesis was conducted at the Department of Cell Biology and Histology of the Academic Medical Centre, University of Amsterdam, The Netherlands. Publication of this thesis was financially supported by: The University of Amsterdam Alzheimer Nederland Internationale Stichting Alzheimer Onderzoek AEGON Cover design: Fanny van Eig-Kievit, De Ontwerpwinkel Printing: Gildeprint Drukkerijen - www.gildeprint.nl Publisher: A. Stargardt Cover: Let’s not forget peptidases in Alzheimer’s disease as important players in the progression of the disease. Also, ‘Let’s not forget’ is the ultimate goal of the research described in this thesis. Copyright © 2014 by A. Stargardt All rights reserved. No part of this publication may be reproduced, stored or transmitted in any way without prior permission from the author. LET’S NOT FORGET PEPTIDASES IN ALZHEIMER’S DISEASE ACADEMISCH PROEFSCHRIFT ter verkrijging van de graad van doctor aan de Universiteit van Amsterdam op gezag van de Rector Magnificus prof. dr. D.C. van den Boom ten overstaan van een door het college voor promoties ingestelde commissie, in het openbaar te verdedigen in de Agnietenkapel op vrijdag 19 december 2014, te 12:00 uur door Anita Stargardt geboren te Amsterdam PROMOTIECOMMISSIE Promotor: Prof. dr. C.J.F. van Noorden Copromotor: Dr. E.A.J. Reits Overige leden: Prof. dr. F. Baas Prof. dr. J.M.F.G. Aerts Prof. dr. P.J. Lucassen Prof. dr. E.M. Hol Prof. dr. J. Verhaagen Prof. dr. R.J.A. Wanders Faculteit der Geneeskunde TABLE OF CONTENTS 1 General introduction and scope of the thesis 6 2 The storm before the quiet: neuronal hyperactivity and Aβ in the presymptomatic 10 stages of Alzheimer’s disease 3 Reduced amyloid-β degradation in early Alzheimer’s disease but not in the 38 APPswePS1dE9 and 3xTg-AD mouse models 4 Quenched Aβ peptide degradation as a diagnostic and prognostic marker for early 60 sporadic Alzheimer’s disease 5 Method of prognosis of Alzheimer’s disease and substrates for use therein 74 6 Kinetic studies of cytoplasmic antigen processing and production of MHC 114 class I ligands 7 Cortical beta amyloid protein triggers an immune response, but no synaptic 128 changes in the APPswe/PSdE9 Alzheimer’s disease mouse model 8 Tripeptidyl peptidase II regulates nuclear levels of phosphorylated ERK1 and ERK2 186 9 Tripeptidyl peptidase II regulates amyloid precursor protein levels, trafficking 242 and processing 10 Summary and conclusions 266 Nederlandse samenvatting 272 Curriculum Vitae 276 Portfolio 277 List of publications 278 Dankwoord 279 1 1 General introduction and scope of the thesis General introduction and scope of the thesis INTRODuCTION 1 Alzheimer’s disease (AD) is the most common form of dementia and is a devastating progressive neurodegenerative disorder currently affecting over 35 million people worldwide. This number is expected to raise because of the growing world population and increasing longevity. Symptoms of AD include impaired memory, personality changes, hallucinations and cognitive decline. Aging is an important risk factor to develop AD; 1 in 3 people over the age of 85 are affected by AD. Cure or disease-modifying therapies are not available and clinical diagnosis is based on impairment of memory and other cognitive functions. AD is hallmarked by extracellular aggregates of Aβ peptides (plaques) and accumulation of these peptides starts decades before the onset of the first symptoms. The Aβ peptide is generated from the amyloid precursor protein (APP). Depending on the processing of APP, either the Aβ peptide is produced (amyloidogenic pathway) or a different, non-toxic peptide (non-amyloidogenic pathway). Understanding of the underlying biological processes has been gained from studies investigating gene mutations in familial AD which is the rare, heritable form of the disease. These gene mutations lead to an increased production of the Aβ peptide, resulting in the formation of plaques and associated symptoms. Knowledge about these gene mutations has also contributed to the generation of AD mouse models. However, most cases of AD (over 95%) are not inherited and are termed ‘sporadic’. It is likely that this form of AD is not caused by excessive production of the Aβ peptide but rather a less efficient clearance. The final result is the same, the Aβ peptide accumulates and leads to plaque formation as observed in the brains of AD patients. The aim of this thesis is to investigate the role of peptidases in AD, as part of the cellular proteostasis network that degrades peptides. We have analyzed which peptidases are able to degrade the Aβ peptide and how their levels and activity change during the development of AD. We have been particularly interested in changes that occur in early stages of AD before the onset of symptoms and whether these changes can be observed in AD mouse models. Understanding of processes that take place in the early stages of the disease is important to allow therapeutic intervention before AD becomes manifest. In addition, we have examined whether changes in peptidase activity can be used to diagnose AD in early stages. SCOPE OF THE THESIS Production and secretion of the Aβ peptide is affected by neuronal activity. In chapter 2, we review 8