NEURAL STEM CELL BIOLOGY AND NEUROGENESIS IN MOUSE MODELS OF AGING AND ALZHEIMER'S DISEASE

Abstract

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 s-amyloid (As) in the cortex and it is believed, that the generation and deposition of As is the leading cause of the disruptions observed in the AD brain. As 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 As deposition, do not develop significant amyloid plaques until past their median lifespan. This limits their availability and the specificity to As 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 As pre-depositing and aged As 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 As, 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 As and morphologically altered. In addition, the population of more differentiated immature neurons appeared to be morphologically unaffected by As. These findings show that As 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.