Age-specific changes in regeneration potential in CNS: molecular analysis on animal model of traumatic spinal cord injury [Elektronische Ressource] / Anne Järve. Gutachter: Hans Werner Müller ; Hermann Aberle

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Sujets

• Biologie

Informations

• Publié par: heinrich-heine-universitat_dusseldorf
• Publié le: 01 janvier 2012
• Nombre de lectures: 22
• Langue: Deutsch
• Poids de l'ouvrage: 5 Mo

Extrait

Age-specific changes in regeneration potential
in CNS: molecular analysis on animal model of
traumatic spinal cord injury


Inaugural-Dissertation


zur Erlangung des Doktorgrades
der Mathematisch-Naturwissenschaftlichen Fakultät
der Heinrich-Heine-Universität Düsseldorf


vorgelegt von

Anne Järve
aus Tallinn


Düsseldorf 2011














Gedruckt mit der Genehmigung der
Mathematisch-Naturwissenschaftlichen Fakultät der
Heinrich-Heine-Universität Düsseldorf




Referent: Prof. Dr. H. W. Müller
Korreferent: Prof. Dr. H. Aberle

Tag der mündlichen Prüfung: 15.12.2011













To my family





















TABLE OF CONTENTS
1. INTRODUCTION ............................................................................................................ 5
1.1. THE AGING CENTRAL NERVOUS SYSTEM (CNS) ...............................................................5
1.2. THE AGING SPINAL CORD ................................................................................................7
1.2.1. Corticospinal tract .....................................................................................................8
1.2.2. Catecholaminergic fibers ...........................................................................................9
1.2.3. Serotonergic fibers ....................................................................................................9
1.2.4. Calcitonin gene-related peptide-immunoreactive fibers ........................................ 10
1.3. TRAUMA IN AGING CNS ................................................................................................ 11
1.3.1. Spinal cord injury (SCI) demographics .................................................................... 11
1.3.2. SCI pathology .......................................................................................................... 12
1.3.3. Lesion scar .............................................................................................................. 13
1.3.4. Effect of age on regeneration processes in aged PNS ............................................ 14
1.3.5. SCI in aged animals ................................................................................................ 15
1.3.6. Genome-wide expression studies of SCI ................................................................. 16
1.4. LESION MODEL AND TREATMENT OF SCI .................................................................... 17
1.4.1. Experimental strategies to suppress collagenous lesion scar ................................ 17
1.4.2. Experimental strategies to increase axonal sprouting ........................................... 18
2. AIM OF THE THESIS .................................................................................................. 19
3. OUTLINE ....................................................................................................................... 20
4. PUBLICATIONS .......................................................................................................... 21
4.1 DIFFERENTIAL EFFECT OF A GING ON AXON SPROUTING AND REGENERATIVE
GROWTH IN SPINAL CORD INJURY ................................................................................. 23
4.2. SDF-1 STIMULATES NEURITE GROWTH ON INHIBITORY CNS MYELIN ......................... 37
4.3. AGE-ASSOCIATED CORTICAL TRANSCRIPTO ME DURING SPINAL CORD REPAIR AFTER
TRAUMA ......................................................................................................................... 47
4.4. SDF-1/CXCL12: ITS ROLE IN SPINAL CORD INJURY ........................................................ 65
4.5. CHEMOKINES IN CNS INJURY AND REPAIR .................................................................... 71
5. GENERAL DISCUSSION ......................................................................................... 108
6. SUMMARY .................................................................................................................. 112
7. ZUSAMMENFASSUNG ............................................................................................ 113
8. REFERENCES ........................................................................................................... 115
9. ABBREVATIONS ...................................................................................................... 122
10. ACKNOWLEDGEMENTS ........................................................................................ 123
4
INTRODUCTION
1. INTRODUCTION
1.1 THE AGING CNS
Aging of brain and spinal cord is not well understood. It remains mystery, how neurons can
stay functional for more than 100 years. Aging affects most prominently the speed of
information processing, which gradually declines throughout the adult life span (Craik et al.,
1994). Age-related memory changes are attributed to reduced activation of the prefrontal
cortex as well as to reduction in white matter and in synapse density which is to some extent
compensated by activating larger cortical areas and even contralateral hemisphere (Hedden
et al., 2004; Bartzokis et al., 2003; Liu et al., 1996; Bourgeois and Rakic, 1996). Other
cognitive aspects are age-stable such as attention span or some get even better such as
emotional components of memory (Cartensen et al., 2011).
There is no significant loss of neurons in most regions of the aging neocortex determined by
the up-to-date stereological methods of neuronal quantification, in contrast to earlier reports
suffering from technical limitations (Burke and Barnes, 2006). Similarly, there is no significant
loss of dendritic branching in the aging hippocampus, moreover it can be even increased in
some hippocampal regions in aged individuals (Buell and Coleman, 1979). Counting of spinal
motoneuronsn of aged individuals and animals has revealed small losses (10-20%), even
when clinical symptoms of hindlimb motor incapacities were apparent (Johnson et al., 1995;
Kawamura et al., 1977; Tomlinson et al., 1977; Hashizume et al., 1988; Xie et al., 2000). Off
note, motoneurons of the 30-months-old rats had lost half of their bouton coverage,
surrounded by glial fibrillary acidic protein (GFAP)-positive processes and showed increased
alpha-calcitonin gene related peptide (CGRP) and detectable growth-associated protein-43
(GAP-43) immunoreactivity (Johnson et al., 1995). This might indicate that normal aging is
accompanied with damage to neuron integrity eliciting responses similar to axon severance
in adults. In contrast, a recent study found increased numbers of neurons in the cervical
spinal cord of aged female rats indicating that neurogenesis persists into old age (Portiansky
et al., 2011). Both the total area occupied by neurons and the number of neurons increased
significantly with age, the latter increase ranging from 16% (cervical segment C6) to 34%
(cervical segment C2). Taking the total number of cervical neurons the age-related increase
ranged from 19% (C6) to 51% (C3), C3 being the segment that grew most in length in the
aged animals. The ratio gray matter area to whole area did not change significantly between
the 30-month-old and 5-month-old rats. Such increase indicates that pre-existing neuroblasts
and/or possible neurogenesis might occur during the entire life span as proliferating neuronal
cells were identified.
5
INTRODUCTION
Gene expression microarrays provide a powerful technology for investigating brain aging as
expression of thousands of genes can be monitored in parallel (Schena et al., 1996; Lockhart
and Barlow, 2001; Lee et al., 2000; Jiang et al., 2001). It appears that aging changes the
expression of ca 4% of genes across different species (Yankner et al., 2008; Lu et al., 2004).
There is a robust age-associated induction of stress response genes such as antioxidant
defense, DNA repair, and immune function. It is possible that the wide-spread
neuroinflammatory response in brain aging is triggered by mitochondrial dysfunction
(Gemma et al., 2002). Aging mitochondria produce reactive oxygen species (ROS) which
may mediate oxidative damage of DNA. In young adult brain, DNA damage is repaired
efficiently, whereas it persists in the aged brain. It is proposed that during normal aging,
neurons likely survive in the presence of unrepaired DNA damage by silencing damaged
areas via transcriptional repression (Yankner et al., 2008). In fact, there are indications that
oxidative DNA damage accumulates in the promotors of a subset of age-downregulated
genes associated with synaptic function, protein transport, and mitochondrial function (Lu et
al., 2004; Ohno et al., 2006). However, some uncertainty remains as to whether the damage
can be random (Yankner et al., 2008). Indeed, aging downregulates genes involved in
mitochondrial function, vesicle-mediated protein transport, synaptic plasticity, including