Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
Löffler, T.
Impact of ApoB-100 expression on cognition and brain pathology in WT and hAPPsl mice
[ Dissertation ] Medical University of Graz; 2012. pp. 121
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- Autor*innen der Med Uni Graz:
- Löffler Tina
- Betreuer*innen:
- Sattler Wolfgang
- Steyrer Ernst
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- Abstract:
- Alzheimer¿s disease (AD), a progressive neurodegenerative disease, highly associated to accumulation and deposition of amyloid beta (Abeta) peptides, is the most common form of dementia. AD can be separated into (i) heritable early-onset AD (EOAD) linked to mutations in the genes for Abeta Precursor Protein (APP) as well as presenilins and (ii) late-onset AD (LOAD) with unknown origin, which accounts for more than 95% of all AD cases. In the last years increasing evidence suggests that hypercholesterolemia and other vascular riskfactors may contribute to the pathogenesis of LOAD. Notably, AD and atherosclerosis share many risk factors, such as diabetes, hypertension and hyperlipidemia. So far it is still under debate to what extent these pathologies contribute to the development of LOAD and how they influence the time course of progression. In this study the effects of apolipoprotein B-100 (ApoB-100) expression, either alone or in combination with cerebral expression of human amyloid precursor protein (hAPP) and in combination with different diets, on cognitive functions and brain pathology were assessed. ApoB-100 animals, overexpressing the entire 43 kb human ApoB-100 gene including its natural human promoter were originally designed as a mouse-model of hyperlipidemia and atherosclerosis. It has been shown that overexpression of human ApoB-100 in mice shifted the lipoprotein profile to a more atherogenic phenotype. ApoB-100 mice were crossbred with the hAPPsl transgenic mouse line, a well described model of familial AD. By this crossbred a vascular risk factor was introduced into the existing AD mouse model to better mimic the situation in elderly people und to investigate the interplay between the two pathologies. Additionally, the impact of a high fat diet on cognitive function and biochemical markers was assessed in animals of every genotype. Results of this study show that ApoB-100 overexpression induces memory decline and increases cerebral lipid peroxidation and amyloid beta levels compared to WT animals. While double-transgenic ApoBxAPP animals did not develop more distinct cognitive deficits than single-transgenic hAPPsl littermates, hApoB-100 expression caused additional pathophysiological properties, indicating that ApoBxAPP mice might better reflect the situation of elderly humans than hAPPsl overexpression alone. The high-fat diet (HFD) seemed to impact on cerebral Abeta clearance. Investigations of cortical mRNA expression patterns underlined the importance of APP in cerebral lipid metabolism and showed a possible connection between APP (with its proteolytic products) and changes in the amount and metabolsim of cerebral cholesterol.