Involvement of endosomal and synaptic A in models of Alzheimer's disease. Willén, Katarina

167 Pages·2017·59.97 MB·English

Involvement of endosomal and synaptic A in models of Alzheimer's disease.
Willén, Katarina
2017
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Citation for published version (APA):
Willén, K. (2017). Involvement of endosomal and synaptic Aβ in models of Alzheimer's disease. [Doctoral Thesis
(compilation), Experimental Dementia Research]. Lund University: Faculty of Medicine.
Total number of authors:
1
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Department of Experimental Medical Science
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Lund University, Faculty of Medicine 9
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Doctoral Dissertation Series 2017:177 6 0
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ISBN 978I-S9S1N-7 1661592--585292-08 7891 7:177
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Involvement of endosomal and synaptic Aβ
in models of Alzheimer's disease

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Involvement of endosomal and synaptic
Aβ in models of Alzheimer's disease

Katarina Willén

DOCTORAL DISSERTATION
by due permission of the Faculty of Medicine, Lund University, Sweden.
To be defended at Segerfalksalen, Wallenberg Neuroscience Center, Lund
University. December 7th 2017 at 13:00.

Faculty opponent
Professor Tobias Hartmann
Saarland University, Homburg, Germany

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Organization Document name
LUND UNIVERSITY Doctoral thesis
Faculty of Medicine,
Dept. of Experimental Medical Science,
Experimental Dementia Research Unit
Date of issue
2017-11-16
Author: Katarina Willén Sponsoring organization
Title and subtitle: Involvement of endosomal and synaptic Aβ in models of Alzheimer's disease
Abstract
Alzheimer’s disease (AD) is a devastating chronic neurodegenerative disease that accounts for 60-80% of all
dementia cases. AD is characterized by progressive decline in cognitive function, aggregated β-amyloid (Aβ) in
amyloid plaques, neurofibrillary tangles (NFTs), dystrophic neurites and loss of synapses and neurons.
However, the earliest changes in the pathology of AD occur in the endocytic pathway with enlarged
endosomes and accumulation of multivesicular bodies (MVBs), lysosomes and autophagic vacuoles. Aβ
accumulates and aggregates particularly in MVBs in synaptic terminals, with signs of synaptic pathology. It is
also well known that synaptic loss is a better correlate of cognitive decline than plaques or NFTs.
Hence, the aim of this thesis was to investigate the role of Aβ in the endocytic pathway and at synapses in AD.
We found that extracellularly applied Aβ1-42 is taken up by primary neurons at synapses, and more by
excitatory CAMKIIα-positive than inhibitory GAD67-positive ones. However, with no clear preference to the
pre- or the post-synaptic site. Aβ1-42 uptake led to enlarged diameter of MVBs and aggregation of Aβ1-42 in
endocytic vesicles. With time, loss of impermeability appeared in the endocytic pathway with oligomeric or
fibrillar structures extending out extracellularly from late endocytic vesicles. Indicative of a role in plaque
formation, markers of the endosomal sorting complexes required for transport (ESCRT)-components were
found in plaques of AD-transgenic mouse models. We also show that APP traffics in the same subpopulation
of MVBs as EGFR and is degraded in the lysosome. Depleting cells of ESCRT-components led to reduced
secretion of Aβ and a marked intracellular accumulation of Aβ and APP. Hence, we suggest a scenario where
disturbances in the MVB pathway, caused by Aβ, or vice versa, lead to a vicious circle of more Aβ
accumulation and aggregation.
We further investigated the native state of this early Aβ aggregation in a mouse model of AD showing that
focal β-sheet formation begins already before the onset of plaques. Here, we also confirmed the findings of Aβ
accumulation leading to disrupted synaptic terminals in AD-transgenic mice brain. Additionally, we present
data supporting the requirement of APP for normal synaptic composition of mature neurons.
Taken together, this work further strengthens the significance of Aβ accumulation and aggregation in the
endocytic pathway at synapses, as an early event in AD pathogenesis.
Key words: Alzheimer’s disease; Amyloid; Multivesicular body; APP
Classification system and/or index terms (if any)
Supplementary bibliographical information Language
ISSN and key title 1652-8220 ISBN 978-91-7619-559-8
Recipient’s notes Number of pages 80 Price
Security classification

I, the undersigned, being the copyright owner of the abstract of the above-mentioned dissertation, hereby grant to all
reference sources permission to publish and disseminate the abstract of the above-mentioned dissertation.

Signature Date 2017-11-0 6
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Involvement of endosomal and synaptic
Aβ in models of Alzheimer's disease

Katarina Willén

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Coverphoto by Katarina Willén

Copyright Katarina Willén and the respective publishers

Faculty of Medicine
Department of Experimental Medical Science

Lund University, Faculty of Medicine Doctoral Dissertation Series 2017:177
ISBN 978-91-7619-559-8
ISSN 1652-8220

Printed in Sweden by Media-Tryck, Lund University
Lund 2017

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