Impairment of insulin signaling pathway in Alzheimer´s Dementia

108 Pages·2012·6.45 MB·English

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
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OUTLOOK ........................................................................................................................................ 96
ACKNOWLEDGEMENT ..................................................................................................................... 98
REFERENCES .................................................................................................................................... 100
CURRICULUM VITAE ..................................................................................................................... 106

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