Jonny Daborg
1
LIST OF PAPERS
This thesis is based on the following studies, referred to in the text by their
Roman numerals.
I.
*
Daborg J.,
*
von Otter M., Sjölander A., Nilsson S., Minthon
L., Gustafson DR., Skoog I., Blennow K., Zetterberg H.
Association of the RAGE G82S polymorphism with
Alzheimer's disease.
J Neural Transm 2010 Jul; 117(7): 861-7.
II.
*
Daborg, J.,
*
Perez-Alcazar, M., Stokowska, A., Wasling, P.,
Björefeldt, A., Beyer, N., Atkins, A.L., Zetterberg, H.,
Carlström, K., Dragunow, M., Clementson Ekdahl, C.,
Hanse, E., Pekna, M. Impaired synaptic elimination and
compensatory homeostatic plasticity in the hippocampus of
mice lacking C3.
In manuscript
III.
Daborg J., Andreasson U., Pekna M., Lautner R., Hanse E.,
Minthon L., Blennow K., Hansson O., Zetterberg H.
Cerebrospinal fluid levels of complement proteins C3, C4
and CR1 in Alzheimer's disease.
J Neural Transm 2012 Jul; 119(7): 789-97.
IV.
Daborg J., Holmgren S., Abramsson A., Andreasson U.,
Zetterberg M., Nilsson S., Minthon L., Skoog I., Blennow
K., Pekna M., Hanse E., Zetterberg H. Association of
complement gene single nucleotide polymorphisms with
Alzheimer's disease.
Submitted to NeuroMolecular Medicine
*
These authors contributed equally.
Synaptic elimination and the complement system in Alzheimer’s disease
2
Jonny Daborg
3
CONTENT
A
BBREVIATIONS
.............................................................................................. 5
1 I
NTRODUCTION
........................................................................................... 7
1.1 Alzheimer’s disease .............................................................................. 7
1.1.1 Diagnosis ....................................................................................... 7
1.1.2 Epidemiology ................................................................................ 8
1.2 Synapses ................................................................................................ 9
1.2.1 Synaptic transmission .................................................................... 9
1.2.2 Synaptic plasticity ....................................................................... 10
1.2.3 Synaptogenesis and synaptic elimination .................................... 12
1.3 Synaptic pathophysiology in AD ........................................................ 14
2 A
IM
........................................................................................................... 16
2.1 The general aim ................................................................................... 16
2.2 The specific aims................................................................................. 16
3 M
ETHODOLOGICAL CONSIDERATIONS
..................................................... 17
3.1 Subjects ............................................................................................... 17
3.1.1 Patients ........................................................................................ 17
3.1.2 Mice ............................................................................................. 17
3.2 Genotyping .......................................................................................... 18
3.3 Electrophysiology ............................................................................... 18
3.3.1 Hippocampal slice preparation .................................................... 18
3.3.2 Extracellular field recordings ...................................................... 19
3.3.3 Whole cell patch clamp recordings ............................................. 21
3.4 Behavioural testing .............................................................................. 22
3.5 Antibody-based assays ........................................................................ 22
3.5.1 Immunohistochemistry ................................................................ 22
3.5.2 Western blot ................................................................................ 23
3.5.3 ELISA .......................................................................................... 23
3.6 qPCR ................................................................................................... 24
Synaptic elimination and the complement system in Alzheimer’s disease
4
3.7 Statistics .............................................................................................. 24
4
SUMMARY OF
R
ESULTS
............................................................................ 26
4.1 Association of RAGE with AD diagnosis ........................................... 26
4.2 Complement mediated synapse elimination in the hippocampus ....... 27
4.3 Complement levels in AD CSF ........................................................... 29
4.4 Complement gene SNPs in AD ........................................................... 30
5 D
ISCUSSION
.............................................................................................. 32
5.1 The events leading to AD – a proposed model ................................... 32
5.1.1 It all starts with Aβ ...................................................................... 32
5.1.2 Altered synaptic plasticity by Aβ ................................................ 33
5.1.3 Synapses are marked for destruction ........................................... 33
5.1.4 Engulfment of synapses by microglia ......................................... 34
5.1.5 Neuronal death ............................................................................ 34
5.1.6 Summary of the model ................................................................ 35
5.2 The present results in relation to the model ........................................ 35
5.3 Final speculations on AD pathogenesis .............................................. 37
6 C
ONCLUSIONS
.......................................................................................... 39
7 F
UTURE PERSPECTIVES
............................................................................. 40
A
CKNOWLEDGEMENT
.................................................................................... 42
R
EFERENCES
.................................................................................................. 43
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