Neuropathological and behavioral alterations in two transgenic mouse models of Alzheimer´s disease
by Julius Nicolai Meißner
Date of Examination:2016-07-19
Date of issue:2016-07-05
Advisor:Prof. Dr. Thomas A. Bayer
Referee:Prof. Dr. Thomas A. Bayer
Referee:Prof. Dr. Tiago Fleming Outeiro
Referee:Prof. Dr. Martin Oppermann
Persistent Address:
http://dx.doi.org/10.53846/goediss-5728
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Abstract
English
According to the influential amyloid cascade hypothesis cerebral accumulation of Aβ is the key event in the pathogenesis of Alzheimer´s disease. Aβ deposits occur as soluble forms, as well as insoluble forms. It is assumed that soluble and intraneuronal Aβ predominantly pro-motes development and progression of the disease. There is a large variety of Aβ species that differ in lengths and the presence of posttranscriptional modifications. The pyroglutamated and truncated isoform AβpE3-42 is an especially toxic variant of the peptide. It was the aim of the present work to extent the knowledge on the role of Aβ in the development of the disease. For this purpose, two transgenic mouse models that address different aspects of the disorder, were characterized by analyzing age neuropathological and behavioral features. In the first part of the thesis, an AD-like phenotype is demonstrated in the murine transgenic TBA42 model, which does not harbor mutated transgenes that are involved in Aβ generation by processing of its precursor protein. It is shown that direct expression of AβpE3-42 in TBA42 mice leads to an age-dependent neurodegeneration in the hippocampal CA1 region of the hippocampus, which is intimately involved in cognition. This leads to a decline in memory function and altered anxiety levels. Moreover, accumulation of AβpE3-42 induces a severe motor deficit, which even precedes the cognitive decline. Thus the toxicity of AβpE3-42 is demonstrated in vivo. Taken together, these findings underline the importance of AβpE3-42 in the etiology and progression of AD and make TBA42 a valid model to study mechanisms of AD progression and potential therapeutic strategies in mice. The majority of AD cases occur sporadically and no overproduction of Aβ is found in these cases. In contrast, sporadic AD is characterized by the impairment of various mechanisms of Aβ clearance. Transport of Aβ across the blood brain is one important mechanism. According to the neurovascular hypothesis of AD an impaired blood brain barrier clearance by LRP1 leads to the retention of Aβ in the brain, resulting in a higher rate of Aβ deposition. In the second part, using the 5xFAD/Lrp1BE-/- model, in which soluble Aβ species are retained in the brain, the effect of a brain endothelial knockout of LRP1 on cognition in an established AD mouse model is demonstrated. While the plaque load and gliosis is unaltered by the knockout, the onset of cognitive impairments is shifted to a younger age in 5xFAD/Lrp1BE-/- mice. Taken together these findings confirm the neurovascular hypothesis of AD, by highlighting the importance of LRP1-mediated blood brain barrier clearance of Aβ. 5xFAD/Lrp1BE-/- mice could be used to test therapeutic approaches, which try to restore the impaired clearance of Aβ across the blood brain barrier. In summary, both the TBA42 and the 5xFAD/Lrp1BE-/- mouse model are valid AD models addressing features of sporadic AD.
Keywords: Alzheimer´s disease; AD; amyloid; Abeta; pyroglutamate; LRP1; 5xFAD; Morris water maze; neurodegeneration; behavior; dementia
