Glial cell reactivity in mouse models reflecting different aspects of Alzheimer's disease

235 Pages·2012·5.03 MB·English

by  Mona Gwendolyn Behrendt

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Glial Cell Reactivity in Mouse Models Reflecting

Different Aspects of Alzheimer’s Disease

Dissertation of the
Graduate School of Systemic Neurosciences of the
Ludwig-Maximilians-University Munich

Submitted by Mona Gwendolyn Behrendt
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Glial Cell Reactivity in Mouse Models Reflecting
Different Aspects of Alzheimer’s Disease

Dissertation of the
Graduate School of Systemic Neurosciences of the
Ludwig-Maximilians-University Munich

Submitted by Mona Gwendolyn Behrendt

Munich, September 2011
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Supervisor: Dr. Leda Dimou
Second expert appraiser: Prof. Dr. Magdalena Götz

Date of oral defense: 12.1.12
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Für meine Eltern
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Abbreviations ..................................................................................V I
Figures .............................................................................................X I
Tables ............................................................................................X III
1 Summary .................................................................................. 1
2 Introduction ............................................................................. 4
2.1 Structural Elements of the Central Nervous System ............. 4
2.2 Glial Cells as Stem Cells in the Central Nervous System ..... 5
2.2.1 Radial Glia- Neural Stem Cells in Development ....... 6
2.2.2 Adult Neural Stem Cells ........................................... 7
2.3 Glial Cells in the Adult Brain .................................................. 9
2.3.1 Astroctyes ............................................................... 10
2.3.1.1 Subsets of Astrocytes .............................. 12
2.3.2 Oligodendrocyte Lineage ........................................ 14
2.3.2.1 Features of NG2-Glia .............................. 16
2.3.2.2 Myelinating Oligodendrocytes .................. 18
2.3.3 Microglia ................................................................. 21
2.4 Glial Cells and their Reaction towards Injury ....................... 22
2.4.1 Reactive Astrocytes ................................................ 24
2.4.2 The Reaction of NG2+ Glia toward Injury ............... 27
2.4.3 The Reaction of Microglia toward Brain Injury ........ 29
2.5 Alzheimer’s Disease – a Chronic Lesion Paradigm ............ 30
2.5.1 Epidemiology .......................................................... 31
2.5.2 Clinical Presentation ............................................... 31
2.5.3 Pathology ............................................................... 32
2.5.3.1 Amyloid Plaques ...................................... 33
2.5.3.2 Tangles .................................................... 34
2.5.3.3 Synapse and Neuron Loss ...................... 34
2.5.3.4 Aβ Cascade Hypothesis .......................... 35
2.5.4 APPPS1- A Mouse Model with Plaque Deposition . 35
II

2.5.5 CK/p25- A Mouse Model with Neuronal Loss ......... 38
2.6 Glial Cells in Alzheimer’s Disease Pathology ...................... 41
2.6.1 Astrocytes ............................................................... 41
3.6.2 Oligodendrocytes ................................................... 42
3.6.3 Microglia ................................................................. 43
2.7 Therapeutical Strategies ..................................................... 44
2.8 Aims of the Study ................................................................ 46
3 Results ................................................................................... 47
3.1 Reactive Gliosis .................................................................. 47
3.1.1 Hypertrophy and Up-regulation of Intermediate
Filaments in APPPS1 Mice ..................................... 47
3.1.2 Up-regulation of Extracellular Matrix Proteins ........ 50
3.1.3 Increased Proliferation upon Chronic Plaque
Deposition .............................................................. 53
3.1.4 Neurosphere Forming Capacity of the Cortical Grey
Matter in APPPS1 .................................................. 57
3.1.5 Self-Renewal of Neurospheres ............................... 58
3.1.6 Neurosphere Formation after Acute Stroke ............ 58
3.1.7 p25 Over Expressing Mice Exhibit Massive
Neurodegeneration ................................................. 60
3.1.8 Reactive Gliosis in CK/p25 mice ............................ 62
3.1.9 Lack of Neurosphere Formation upon Neuronal Loss
............................................................................... 64
3.1.10 Proliferation of Glial Cells in CK/p25 Mice ............. 65
3.1.11 pcJun and pJNK Expression of Reactive Astrocytes
in Different Lesion Paradigms ................................ 69
3.1.12 Expression of Olig2 in Astrocytes in Different Lesion
Paradigms .............................................................. 72
3.1.13 Increased Expression of Cyclin D1 in Astrocytes in
Different Lesion Paradigms .................................... 74
3.1.14 Invasion of Blood-derived Cells in APPPS1 and
CK/p25 Mice ........................................................... 76
3.1.15 Unchanged Blood Brain Barrier Integrity in APPPS1
and CK/p25 Mice .................................................... 78
3.2 Reactivity of Oligodendrocyte Progenitors upon Chronic
Amyloid Plaque Deposition ................................................. 80
3.2.1 Focal Loss of Myelin in Plaque Core Areas ............ 80
3.2.2 Analysis of Myelin Protein Amounts ....................... 81
3.2.3 Increase in Myelin Aberrations in APPPS1 Mice .... 83