The 37kDa/67kDa laminin receptor LRP/LR as a molecular target in neurodegenerative diseases [Elektronische Ressource] / Heike Pflanz
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The 37kDa/67kDa laminin receptor LRP/LR as a molecular target in neurodegenerative diseases [Elektronische Ressource] / Heike Pflanz

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DissertationZur Erlangung des DoktorgradesDer Fakultät für Chemie und PharmazieDer Ludwig-Maximilians-Universität MünchenThe 37kDa/67kDa Laminin Receptor LRP/LRas a molecular target in neurodegenerative diseasesHeike PflanzausLüneburg2009ErklärungDiese Dissertation wurde im Sinne von §13 Abs. 3 der Promotionsordnung vom 29. Januar1998 von Prof. Dr. Stefan Weiss betreut.Ehrenwörtliche VersicherungDiese Dissertation wurde selbständig, ohne unerlaubte Hilfe erarbeitet.München, am 30.03.2009_____________________Heike PflanzDissertation eingereicht am 30. März 20091. Gutachter: Prof. Dr. Stefan Weiss2. Gutachter: Prof. Dr. Dr. Hans A. KretzschmarMündliche Prüfung am 15. Mai 2009Die vorliegende Arbeit wurde in der Zeit von Mai 2006 bis März 2009 im Labor von Prof. Dr.Stefan Weiss am Genzentrum der Ludwig-Maximilians-Universität München angefertigt.Im Verlauf dieser Arbeit wurden folgende Originalpublikationen veröffentlicht bzw.eingereicht:Nikles, D., Vana, K., Gauczynski, S., Knetsch, H., Ludewigs, H. and Weiss, S., Subcellularlocalization of prion proteins and the 37kDa/67kDa laminin receptor fused to fluorescentproteins. Biochim Biophys Acta 2008. 5: 335-340.Pflanz, H., Vana, K., Mitteregger, G., Pace, C. Messow, D., Sedlaczek, C., Nikles, D.,Kretzschmar, H. A. and Weiss, S. F.

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Publié le 01 janvier 2009
Nombre de lectures 273
Langue Deutsch
Poids de l'ouvrage 8 Mo

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Dissertation
Zur Erlangung des Doktorgrades
Der Fakultät für Chemie und Pharmazie
Der Ludwig-Maximilians-Universität München
The 37kDa/67kDa Laminin Receptor LRP/LR
as a molecular target in neurodegenerative diseases
Heike Pflanz
aus
Lüneburg
2009Erklärung
Diese Dissertation wurde im Sinne von §13 Abs. 3 der Promotionsordnung vom 29. Januar
1998 von Prof. Dr. Stefan Weiss betreut.
Ehrenwörtliche Versicherung
Diese Dissertation wurde selbständig, ohne unerlaubte Hilfe erarbeitet.
München, am 30.03.2009
_____________________
Heike Pflanz
Dissertation eingereicht am 30. März 2009
1. Gutachter: Prof. Dr. Stefan Weiss
2. Gutachter: Prof. Dr. Dr. Hans A. Kretzschmar
Mündliche Prüfung am 15. Mai 2009Die vorliegende Arbeit wurde in der Zeit von Mai 2006 bis März 2009 im Labor von Prof. Dr.
Stefan Weiss am Genzentrum der Ludwig-Maximilians-Universität München angefertigt.
Im Verlauf dieser Arbeit wurden folgende Originalpublikationen veröffentlicht bzw.
eingereicht:
Nikles, D., Vana, K., Gauczynski, S., Knetsch, H., Ludewigs, H. and Weiss, S., Subcellular
localization of prion proteins and the 37kDa/67kDa laminin receptor fused to fluorescent
proteins. Biochim Biophys Acta 2008. 5: 335-340.
Pflanz, H., Vana, K., Mitteregger, G., Pace, C. Messow, D., Sedlaczek, C., Nikles, D.,
Kretzschmar, H. A. and Weiss, S. F., Microinjection of lentiviral vectors expressing small
interfering RNAs directed against laminin receptor precursor mRNA prolongs the pre-clinical
phase in scrapie-infected mice. J Gen Virol 2009. 1: 269-274.
Pflanz, H., Vana, K., Mitteregger, G., Renner-Müller, I., Pace, C., Küchenhoff, H.,
Kretzschmar, H. A., Wolf, E., Weiss, S., Scrapie-infected transgenic mice expressing a
laminin receptor decoy mutant reveal a prolonged incubation time associated with low levels
of PrPres. J Mol Biol, in press
Pflanz, H., Bergmann, A.-K., Dimitriadis, C., Knackmuss, S., Reusch, U., Zuber, C., Haass,
C., Little, M., Weiss, S., The LRP-specific antibody IgG1 iS18 reduced Amyloid β secretion
in APP-expressing HEK293FT cells. Nature. submittedIm Verlauf wurden folgende Übersichtsartikel publiziert:
Zuber, C., Ludewigs, H. and Weiss, S., Therapeutic approaches targeting the prion receptor
LRP/LR. Vet Microbiol 2007. 4: 387-393.
Ludewigs, H., Zuber, C., Vana, K., Nikles, D., Zerr, I. and Weiss, S., Therapeutic approaches
for prion disorders. Expert Rev Anti Infect Ther 2007. 4: 613-630.
Vana K., Zuber C., Pflanz H., Kolodziejczak D., Zemora G., Bergmann A. K. and Weiss S.,
LRP/LR as an alternative promising target in therapy of prion diseases, Alzheimer's disease
and cancer. Infect Disord Drug Targets 2009. 1: 69-80.
Vorträge auf Konferenzen
• NoE Neuroprion Meeting 14. März 2008, München
• NoE Neuroprion Meeting 10. Oktober 2008, MadridAAckncknowleowledgedgememenntsts
I would like to thank Prof. Dr. Stefan Weiss for the great opportunity to work in the field of
biochemistry and to intensively study neurological disorders, especially prion diseases and
Alzheimer´s disease. Such a position is not easy to find for a pharmacist. I appreciate the
opportunity to visit international congresses and to give oral presentations. Finally, I am
grateful for the creation of the first certificate.
I want to thank Prof. Dr. Dr. Hans A. Kretzschmar for his continuous support, for the
attendance in my thesis committee and for the creation of the second certificate.
I would like to thank Prof. Dr. Roland Beckmann, Prof. Dr. Angelika Vollmar, Prof. Dr.
Dietmar Martin and Prof. Dr. Klaus Förstemann for attending my thesis committee.
I am grateful to Dr. Gerda Mitteregger for helpful advices in experimental setups and her
reliability regarding the animal experiments.
I want to thank all group members of the AG Weiss, particularly Dr. Karen Vana, for
developing the projects, I took over, for always being there and caring for a optimistic
atmosphere. Especially, I want to thank Dr. Chantal Zuber who was there from the beginning
to the last day. I am grateful for her big knowledge, for always being open minded, the long
discussions and continuous help. A special thank goes to Dr. Daphne Nikles for having an
idea to solve each and every problem, for spreading high spirits even if the experiments didn´t
work out.
I am grateful to Ann-Katrin Bergmann, Christoph Dimitriadis and André Heuer for their
enthusiastic engagement and pushing forward the Alzheimer project.
I thank Georgeta Zemora, Katharina Häussermann, Cilli Sedlaczek, Dominika (El Dome)
Kolodziejczak, Benjamin (the consultant) Hackner, Katja Vlasova and Jennifer Hentrich for
the nice atmosphere in the lab, even in the times when only girls were around, for nice
cocktail and cinema evenings.I would like to thank Stephanie Koch and Franziska Siegel for the nice time in Frankfurt, for
the best study group ever and for still being my friends today. And I want to thank Stephanie
Schmelcher-Mändle for distracting me from work so often and providing kids to distract me
from everything else.
I am grateful to Ingo Pflanz for his support and objective opinion, for listening to endless lab-
stories, for keeping an eye on my sometimes never-ending working hours and for being my
helpdesk in every sense.
Finally, I want to thank my family, especially my parents for giving me the opportunity to
study, for their continuous support and their confidence in my decisions.TABLE OF CONTENTS
SUMMARY
CHAPTER I
Therapeutic approaches for prion disorders
CHAPTER II
Therapeutic approaches targeting the prion receptor LRP/LR
CHAPTER III
LRP/LR as an alternative promising target in therapy of prion diseases, Alzheimer´s
disease and cancer
CHAPTER IV
Scrapie-infected transgenic mice expressing a laminin receptor decoy mutant reveal a
prolonged incubation time associated with low levels of PrPres
CHAPTER V
Microinjection of lentiviral vectors expressing small interfering RNAs directed against
laminin receptor precursor mRNA prolongs the pre-clinical phase in scrapie-infected
mice
CHAPTER VI
The laminin receptor specific antibody IgG1 iS18 impedes amyloid β release from
human embryonic kidney cells
CHAPTER VII
Subcellular localization of prion proteins and the 37kDa/67kDa laminin receptor
fused to fluorescent proteins
ABBREVIATIONS
CURRICULUM VITAESummary
Prion disorders and Alzheimer´s disease (AD) both belong to the group of neurodegenerative
diseases and share distinct neuropathological patterns. The key event in prion diseases, such
as Creutzfeldt-Jakob disease (CJD) in humans or bovine spongiform encephalopathy (BSE) in
ccattle, is the conversion of the host encoded cellular prion protein (PrP ) to the disease
Scassociated misfolded isoform PrP scrapie (PrP ), predominantly accumulating in the brain. In
AD the causative agent and the main component of the amyloid plaques is the Amyloid β
peptide, emerged from the enzymatic processing of the Amyloid β precursor protein (APP).
These protein aggregates lead to neuronal death of the affected individual. So far, there is no
therapy available to cure or stall the progression of both diseases, although a lot of efforts
have been driven to develop curative or palliative therapies.
Recently, the 37kDa/67kDa non-integrin laminin receptor LRP/LR has been identified as a
Screceptor for the cellular prion protein and the pathogenic isoform PrP . Fluorescent labeled
LRP- and PrP-molecules co-localize on the cell surface and in the perinuclear compartment.
Furthermore, a fluorescent PrP-mutant lacking the signal sequence partly co-localizes with
fluorescence labeled LRP in the nucleus. These results implicate an involvement of LRP/LR
in the cellular trafficking of the prion protein.
A series of therapeutic strategies for the treatment of prion diseases targeting LRP/LR have
been conducted. Downregulation of LRP/LR by RNAi and the generation of a laminin
receptor decoy mutant represent alternative promising approaches. Microinjection of lentiviral
vectors encoding for siRNAs directed against the LRP mRNA into the hippocampus resulted
in a significant prolongation of the pre-clinical phase in scrapie infected mice. Transgenic
mice expressing a laminin receptor decoy mutant show a significantly prolonged incubation
time after prion inoculation. Therefore, LRP/LR represents a promising molecular target for
the development of prion disease therapeutics.
cVery recently, PrP has been shown to directly regulate β -secretase activity, which
participates in the amyloidogenic cleavage process of APP, generating the soluble APPβ
c(sAPPβ ) and the AD-associated Amyloid β peptides (Aβ ). Furthermore, PrP mediates
cimpairment of synaptic plasticity by amyloid-β oligomers. The prion receptor LRP/LR, PrP
and APP all localize at the cell surface. Treatment of HEK293FT cells with the LRP/LR-
specific antibody IgG1-iS18 resulted in a significant reduction of the Aβ release and the
sAPPβ shedding by 99%, respectively, suggesting that LRP/LR contributes to both processes
by promoting the β-secretase. LRP/LR specific pharmaceuticals such as antibodies may have
therapeutic potential for the treatment of Alzheimer’s Disease.Chapter I
Therapeutic approaches for prion disorders
p

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