Analyse neurodegenerativer Prozesse im Gyrus Dentatus im Tg4-42-Mausmodell der Alzheimerdemenz

Abstract

Alzheimer's disease is a neurodegenerative disease and the most common form of dementia. Hyperphosphorylated tau and extracellular Aβ deposits are classical neuropathological hallmarks of AD. In addition to extracellular, the intracellular Aβ-accumulation events are considered to be important factors in the occurrence of specific AD, as their occurrence is strongly associated with neuropathological abnormalities. In addition to the classical neuropathological hallmarks, a strongly increased loss of neurons and a noticeably restricted rate of neurogenesis and neuroinflammation can be detected in brain regions specific for AD. Most transgenic mouse models function on the basis of mutations in the amyloid precursor protein or presenilin to reach an enhanced Aβ expression. In contrast, the transgenic mouse model Tg4-42 works without mutations in APP or presenilin and leads to an overexpression of intracellularly accumulating Aβ4-42. This is of particular importance, as it allows the sole neuropathological properties of Aβ4-42 to be investigated. This study shows, that the Tg4-42 mouse model showed significant neuropathological changes in the dentate gyrus. Especially a strong loss of neurons could be detected in this brain region. Loss of neurons was inversely associated with age. Mice of the ages of five and six months showed a significant loss of neurons compared to younger transgenic mice. In addition to changes in the number of neurons, a decrease in doublecortin-positive neurons could be observed. Using doublecortin as a marker, it is possible to get conclusions about the neurogenesis. Neurogenesis decreased equally with the loss of neurons in the older rodents. Also, mice of the ages of five and six months showed a significant decrease in neurogenesis rates compared to younger animals. Interestingly, changes in volume of the dentate gyrus could not be detected, although the rate of neurogenesis was decreasing and there was a significant loss of neurons to be found. Additionally, transgenic mice showed an enhanced gliosis in comparison to wild type mice, which was determined by GFAP positive astrocytes. Data from the immunohistochemical analysis of gliosis correlated with data from GFAP gene expression. The dentate gyrus is of special significance concerning the symptoms of AD in two respects. Firstly, the dentate gyrus is part of the hippocampus and therefore one of the first brain regions affected by AD. Secondly, the dentate gyrus is one of two regions in the adult brain, where neurogenesis could be detected. For this reason, the dentate gyrus is an integral part of processes of neural plasticity, memory formation and learning in the adult brain. A decreased neurogenesis and a massive loss of neurons in this region lead to limitations in these qualities and subsequently to symptoms typical for AD. Furthermore, the pathologies documented in this study explain the behavioral problems previously observed in Tg4-42 mice, such as spatial orientation disorder. With the results of this study, further insights into the Tg4-42 mouse model and the importance of Aβ4-42 for the pathogenesis of AD were obtained. It could be shown that not only the CA1 region but also the dentate gyrus shows significant neuropathological abnormalities due to the influence of Aβ4-42. It is conceivable that, as in the CA1 region, these abnormalities may be due to intracellular Aβ4-42 accumulations or expression of the transgene in the CA1 region due to secreted, soluble Aβ4-42 peptides. A direct proof of intracellular accumulation is currently not possible due to the dense neuronal network in the dentate gyrus.