Auswirkung von Enriched Environment auf hippocampalen Nervenzellverlust und Gedächtnisfunktionen im Mausmodell Tg4-42
Effects of enriched environment on hippocampal neuronal loss and memory functions in the mouse model Tg4-42.
von Andreas Martin Brauß
Datum der mündl. Prüfung:2023-02-28
Betreuer:Prof. Dr. Oliver Wirths
Gutachter:Prof. Dr. Bernhard Reuß
Gutachter:Prof. Dr. Ralf Dressel
EnglischN-truncated Aβ4-42 is one of the Aβ isoforms most frequently present in the brains of patients suffering from Alzheimer's disease. It exhibits an increased propensity for aggregation and increased toxicity, which can lead to neuronal death in vitro as well as in vivo. The mouse model Tg4-42 expresses specifically Aβ4-42 and exhibits an age- and gene-dose dependantvneuronal cell loss primarily in the CA1 pyramidal cell layer of the hippocampus and progressive loss of memory functions. In this work, it was shown that Tg4-42hom animals at five months of age do not yet show a clearly measurable limitation in spatial reference memory, as they still show some preference for target quadrants in the Probe Trial of the MWM. However, in a stereological examination, a loss of neurons of the order of nearly 43% is already seen in the CA1 region at this time. From the age of six months, Tg4-42hom mice show pronounced limitations in spatial learning, which is reflected in a lack of preference for the target quadrant in the Probe Trial of MWM. This is associated with a neuronal cell loss in CA1of nearly 50% in six-month-old animals and over 52% in seven-month-old mice. Thus, a nerve cell loss of approximately 50% in CA1 appears to be the threshold for intact spatial reference memory. These findings underscore the importance of N-truncated Aβ4-42 with respect to the pathogenesis of pathogenesis of Alzheimer's disease and support the modified amyloid hypothesis, since in the Tg4-42hom mouse model intraneuronal accumulation of Aβ4-42 leads to a pronounced hippocampal neurodegeneration and concomitant limitations of spatial memory functions. Physical activity and cognitive stimulation could be identified in metastudies as modifiable factors with great potential in terms of risk reduction of AD. In animal models, this stimulation can be simulated and studied by the concept of EE. Tg4-42hom animals housed in the EE from two months of age show still functioning spatial reference memory at six months of age compared to standard housing (SH) animals, as expressed by a significant preference of the target quadrant in the Probe Trial of the MWM. Compared with SH animals, this is associated with a highly significant delayed hippocampal neuronal cell loss in CA1, by approximately 41% compared with wild-type animals of the same age. The cellular or molecular causes are not yet clearly understood, but appear to be associated with increased hippocampal neurogenesis and the induction of growth factors and cytoprotective proteins. Thus, it is shown that EE or the associated increased physical activity over a longer period of time has a positive preventive influence on neuronal cell loss in the pyramidal cell layer and associated losses of spatial reference memory. Thus, the prospective study design used in this work supports the epidemiological data obtained from retrospective human studies. Likewise, the importance of physical activity as a simple modifiable risk factor of Alzheimer's disease.
Keywords: Alzheimer; Enriched Environment