Neural stem cell biology and neurogenesis in mouse models of aging and Alzheimer's disease

摘要

The etiology of Alzheimer’s disease (AD) remains a great challenge for neurological research.udExtensive investigations for almost one hundred years have led to profound insights of theudpathological and molecular mechanisms that affect the AD brain, and there are severaludhypotheses about what causes the characteristic AD related dementia. The focus has fallenudincreasingly on the deposition of ß-amyloid (Aß) in the cortex and it is believed, that theudgeneration and deposition of Aß is the leading cause of the disruptions observed in the ADudbrain. Aß has been shown to provoke neuron death, decreased synaptic plasticity, aberrantudsprouting of growing axons, chronic inflammation and hyper-phosphorylation of tau.udIn recent years, research on adult neurogenesis in the mammalian brain has led to surprisingudfindings: new neurons are added daily to specific regions of the brain and growing evidenceudsuggests that these new neurons play a critical role for learning and memory, mood and, to audlimited amount, repair of damaged cortical areas. All of these functionalities of neurogenesisudare affected in AD patients and the question must be raised, if in the AD brain, neurogenesisudis directly disturbed. Defects in neural stem cell biology might significantly contribute to ADuddementia and the examination of the relationship of AD lesions and neural stem cell biologyudmight provide new insights for the understanding and treatment of AD.udOnly recently has it become possible to investigate neural stem cell biology in the AD brain.udThis is partly because only recent findings revealed the function of adult neural stem cells, butudalso because animal models for AD have only been available for few years. However, mostudAD mouse models, which are genetically engineered for Aß deposition, do not developudsignificant amyloid plaques until past their median lifespan. This limits their availability andudthe specificity to Aß is reduced due to accompanying age effects.udIn a first study of this thesis, age related changes of neurogenesis were investigated byudmonitoring the progressive stages of hippocampal neurogenesis: proliferation, survival anduddifferentiation, in four different age groups of wild type C57BL/6J mice. Net-neurogenesisudwas rapidly reduced in adult compared to young mice, but remained stable at a low level inudaged and senescent mice. This effect could be attributed mostly to an age related decline ofudproliferation with a concomitant increase of survival rates in aged mice. These results suggestudthat neurogenesis in aged mice remains as functional as in adult mice, although the plasticityududof the neurogenic system appears to be reduced compared to young mice. The finding that audreduced caloric diet, a treatment known to reduce age related defects, did not have an effectudon neurogenesis confirmed the finding that neurogenesis is not impaired in aged miceudcompared to adult mice.udIn a second study neurogenesis was studied in APP23 mice, a transgenic AD mouse modeludwith progressive amyloid plaque load. Adult Aß pre-depositing and aged Aß high-depositingudmice were investigated. Surprisingly, aged APP23 mice showed an increased number of newudneurons in the hippocampus compared to age matching controls. For a closer investigation ofudthe interaction of neural stem cells and Aß, we crossed mice expressing GFP under a stem celludspecific promoter with a new AD mouse model with cortical plaque deposition in earlyudadulthood. Stem cells were reduced in numbers, strongly attracted to Aß and morphologicallyudaltered. In addition, the population of more differentiated immature neurons appeared to beudmorphologically unaffected by Aß. These findings show that Aß affects neural stem celludbiology concomitant with an up-regulation of neurogenesis.udSeveral reports claim that stem cells from the periphery are able to cross the blood brainudbarrier and are able trans-differentiate to the neuronal lineage. It has also been shown, that theudnumber of cells immigrating from the periphery increases in AD mouse models. Thus, in audthird study we investigated if stem cells from the peripheral hematopoietic system couldudparticipate in the repair or replacement of the damaged neuronal tissue. APP23 mice wereuddeprived of their immune system by gamma irradiation and later reconstituted withudgenetically marked hematopoietic stem cells. We found a large number of these cells invadingudthe brains of aged APP23 mice, but cell fate analysis revealed that these cells matured toudmacrophages or T-cells, but none differentiated towards the neuronal lineage. We concludeudthat the hematopoietic system is involved in the immune response in the brain, but we foundudno evidence that it is involved the in repair of the damaged network or in the alterations ofudneural stem cell biology described above.udIn conclusion, the results of the present thesis provide evidence of a defective behavior ofudneural stem cells in the amyloidogenic brain, but also unveil the limitations in the functionudand ability of neural stem cells in the aged brain.