Ermini, Florian V.. Neural stem cell biology and neurogenesis in mouse models of aging and Alzheimer's disease. 2006, PhD Thesis, University of Basel, Faculty of Science.
Official URL: http://edoc.unibas.ch/diss/DissB_7375
The etiology of Alzheimer’s disease (AD) remains a great challenge for neurological research.
Extensive investigations for almost one hundred years have led to profound insights of the
pathological and molecular mechanisms that affect the AD brain, and there are several
hypotheses about what causes the characteristic AD related dementia. The focus has fallen
increasingly on the deposition of ß-amyloid (Aß) in the cortex and it is believed, that the
generation and deposition of Aß is the leading cause of the disruptions observed in the AD
brain. Aß has been shown to provoke neuron death, decreased synaptic plasticity, aberrant
sprouting of growing axons, chronic inflammation and hyper-phosphorylation of tau.
In recent years, research on adult neurogenesis in the mammalian brain has led to surprising
findings: new neurons are added daily to specific regions of the brain and growing evidence
suggests that these new neurons play a critical role for learning and memory, mood and, to a
limited amount, repair of damaged cortical areas. All of these functionalities of neurogenesis
are affected in AD patients and the question must be raised, if in the AD brain, neurogenesis
is directly disturbed. Defects in neural stem cell biology might significantly contribute to AD
dementia and the examination of the relationship of AD lesions and neural stem cell biology
might provide new insights for the understanding and treatment of AD.
Only recently has it become possible to investigate neural stem cell biology in the AD brain.
This is partly because only recent findings revealed the function of adult neural stem cells, but
also because animal models for AD have only been available for few years. However, most
AD mouse models, which are genetically engineered for Aß deposition, do not develop
significant amyloid plaques until past their median lifespan. This limits their availability and
the specificity to Aß is reduced due to accompanying age effects.
In a first study of this thesis, age related changes of neurogenesis were investigated by
monitoring the progressive stages of hippocampal neurogenesis: proliferation, survival and
differentiation, in four different age groups of wild type C57BL/6J mice. Net-neurogenesis
was rapidly reduced in adult compared to young mice, but remained stable at a low level in
aged and senescent mice. This effect could be attributed mostly to an age related decline of
proliferation with a concomitant increase of survival rates in aged mice. These results suggest
that neurogenesis in aged mice remains as functional as in adult mice, although the plasticity
of the neurogenic system appears to be reduced compared to young mice. The finding that a
reduced caloric diet, a treatment known to reduce age related defects, did not have an effect
on neurogenesis confirmed the finding that neurogenesis is not impaired in aged mice
compared to adult mice.
In a second study neurogenesis was studied in APP23 mice, a transgenic AD mouse model
with progressive amyloid plaque load. Adult Aß pre-depositing and aged Aß high-depositing
mice were investigated. Surprisingly, aged APP23 mice showed an increased number of new
neurons in the hippocampus compared to age matching controls. For a closer investigation of
the interaction of neural stem cells and Aß, we crossed mice expressing GFP under a stem cell
specific promoter with a new AD mouse model with cortical plaque deposition in early
adulthood. Stem cells were reduced in numbers, strongly attracted to Aß and morphologically
altered. In addition, the population of more differentiated immature neurons appeared to be
morphologically unaffected by Aß. These findings show that Aß affects neural stem cell
biology concomitant with an up-regulation of neurogenesis.
Several reports claim that stem cells from the periphery are able to cross the blood brain
barrier and are able trans-differentiate to the neuronal lineage. It has also been shown, that the
number of cells immigrating from the periphery increases in AD mouse models. Thus, in a
third study we investigated if stem cells from the peripheral hematopoietic system could
participate in the repair or replacement of the damaged neuronal tissue. APP23 mice were
deprived of their immune system by gamma irradiation and later reconstituted with
genetically marked hematopoietic stem cells. We found a large number of these cells invading
the brains of aged APP23 mice, but cell fate analysis revealed that these cells matured to
macrophages or T-cells, but none differentiated towards the neuronal lineage. We conclude
that the hematopoietic system is involved in the immune response in the brain, but we found
no evidence that it is involved the in repair of the damaged network or in the alterations of
neural stem cell biology described above.
In conclusion, the results of the present thesis provide evidence of a defective behavior of
neural stem cells in the amyloidogenic brain, but also unveil the limitations in the function
and ability of neural stem cells in the aged brain.
|Advisors:||Rüegg, Markus A.|
|Committee Members:||Jucker, Mathias K. and Staufenbiel, Matthias|
|Faculties and Departments:||05 Faculty of Science > Departement Biozentrum > Neurobiology > Pharmacology/Neurobiology (Rüegg)|
|Bibsysno:||Link to catalogue|
|Number of Pages:||104|
|Last Modified:||11 Mar 2009 12:29|
|Deposited On:||13 Feb 2009 16:25|
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