Impairment of insulin signaling pathway in Alzheimer´s Dementia PDF
Preview Impairment of insulin signaling pathway in Alzheimer´s Dementia
Für meine geliebten Eltern Rosi und Dieter Bartl Impairment of insulin signaling pathway in Alzheimer’s disease Beeinträchtigung des Insulinsignalweges bei Alzheimer Demenz Doctoral thesis for a science doctoral degree at Julius-Maximilians-Universität Würzburg Section: Neurobiology Submitted by Jasmin Bartl from Böblingen Würzburg 2012 Submitted on: ……………………………………………………………………. Office stamp Members of the graduation committee: Chairperson: Prof. Dr. Thomas Dandekar (University of Würzburg) Primary Supervisor: PD Dr. Edna Grünblatt (University of Zürich) Supervisor (Second): Prof. Dr. Erich Buchner (University of Würzburg) Date of Public Defence: ……………………………….. Date of receipt of Certificates: ………………………… AFFIDAVIT (EIDESSTATTLICHE ERKLÄRUNG) According §4 Abs. 3 Ziff. 3, 5 and 8 of the “Promotionsordnung der Julius-Maximilians-Universität Würzburg“ I hereby declare that my thesis entitled “Impairment of insulin signaling pathway in Alzheimer’s disease” is the result of my own work. I did not receive any help or support from commercial consultants. All sources and / or materials applied are listed and specified in the thesis. Furthermore, I verify that this thesis has not yet been submitted as part of another examination process neither in identical nor in similar form. Zürich, ……………………………………………………. “Dissertation Based on Several Published Manuscripts“ Statement on individual author contributions Publication: Bartl, J., C. J. Scholz, M. Hinterberger, S. Jungwirth, I. Wichart, M. K. Rainer, S. Kneitz, W. Danielczyk, K. H. Tragl, P. Fischer, P. Riederer, and E. Grünblatt (2011) Disorder-specific effects of polymorphisms at opposing ends of the Insulin Degrading Enzyme gene. BMC Med Genet 12:151.(DOI 1471-2350-12-151 /10.1186/1471-2350-12-151) Participated in Author-Initials, Responsibility decreasing from left to right Study Design ED PR Data Collection MH SJ IW MKR WD KHT Data-Analysis and Interpretation CJS JB SK PF Manuscripte writing JB CJS I confirm that I have obtained permission from the co-authors see signature below: C.J. Scholz M. Hinterberger S. Jungwirth I. Wichart M.K. Rainer S. Kneitz W. Danielczyk K.H. Tragl P. Fischer P. Riederer E. Grünblatt Publication: Bartl J, Monoranu CM, Wagner AK, Kolter J, Riederer P, Grünblatt E. (2012) Alzheimer's disease and type 2 diabetes: Two diseases, one common link? World J Biol Psychiatry. 2012 Feb 14. IN PRESS Participated in Author-Initials, Responsibility decreasing from left to right Study Design ED PR JB Data Collection JB AKW JK Data-Analysis and Interpretation JB AKW JK Manuscripte writing JB ED PR I confirm that I have obtained permission from the co-authors see signature below: C.M. Monoranu A.K. Wagner J. Kolter P. Riederer E. Grünblatt Publication: Bartl J., Meyer A., Brendler S., Riederer P., Grünblatt E.(2012) Different effects of soluble and aggregated Amyloid β on gene/ protein expression and enzyme 42 activity involved in insulin and APP pathways submitted to journal of neural transmission Participated in Author-Initials, Responsibility decreasing from left to right Study Design JB ED Data Collection AM SB JB Data-Analysis and Interpretation JB ED PR Manuscripte writing JB ED PR I confirm that I have obtained permission from the co-authors signature below: A. Meyer S. Brendler P. Riederer E. Grünblatt I also confirm my primary supervisor’s acceptance. ___________________________________________________________________________ Doctoral Researcher‟s Name Date Place Signature Altern ist ein hochinteressanter Vorgang: Man denkt und denkt und denkt – plötzlich kann man sich an nichts mehr erinnern. (Ephraim Kishon, Israelischer Schriftsteller) INDEX TABLE OF CONTENTS LIST OF FIGURES AND TABLES ..................................................................................................... 11 ABBREVATION INDEX ..................................................................................................................... 12 ZUSAMMENFASSUNG ...................................................................................................................... 14 SUMMARY .......................................................................................................................................... 16 INTRODUCTION ................................................................................................................................. 18 GENERAL INTRODUCTION ........................................................................................................... 18 EARLY AND LATE ONSET OF ALZHEIMER`S DISEASE .............................................................. 19 AMYLOID β CASCADE HYPOTHESIS ............................................................................................ 20 NEUROTOXICITY OF DIFFERENT AMYLOID β SPECIES .......................................................... 22 ALZHEIMER’S DISEASE=TYPE 3 DIABETES? ............................................................................. 25 Role of peroxisome proliferator-activated receptor γ ................................................................... 28 THESIS OUTLINE ............................................................................................................................... 30 AIMS AND QUESTIONS ................................................................................................................... 30 OVERVIEW OF MANUSCRIPTS ....................................................................................................... 32 ABSTRACT MANUSCRIPT I ............................................................................................................ 32 ABSTRACT MANUSCRIPT II ........................................................................................................... 33 ABSTRACT MANUSCRIPT III .......................................................................................................... 34 MANUSCRIPT I ................................................................................................................................ 36 MANUSCRIPT II ............................................................................................................................... 46 MANUSCRIPT III.............................................................................................................................. 60 DETAILED METHODS ....................................................................................................................... 82 MANUSCRIPT I ................................................................................................................................ 82 MANUSCRIPT II ............................................................................................................................... 85 MANUSCRIPT III.............................................................................................................................. 87 DISCUSSION ....................................................................................................................................... 90 GENERAL DISCUSSION .................................................................................................................. 90 Insulin degrading enzyme gene- a link of Alzheimer’s disease with type 2 diabetes mellitus? ..... 90 Common histopathological features of Alzheimer’s disease and type 2 diabetes mellitus ........... 92 Aggregation form of amyloid β influences gene/ protein expression .......................................... 94 42 OUTLOOK ........................................................................................................................................ 96 ACKNOWLEDGEMENT ..................................................................................................................... 98 REFERENCES .................................................................................................................................... 100 CURRICULUM VITAE ..................................................................................................................... 106 10
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