Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
Babalola, J.
Neuroprotective effects of Astaxanthin in preclinical models of Alzheimer's disease
PhD-Studium (Doctor of Philosophy); Humanmedizin; [ Dissertation ] Medizinische Universität Graz; 2023. pp. 251
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- Autor*innen der Med Uni Graz:
- Betreuer*innen:
- Höfler Gerald
- Leitinger Gerd
- Altmetrics:
- Abstract:
- ABSTRACT Background: Alzheimer’s disease (AD) is a multi-factorial degenerative disease of the brain thought to be caused by misfolding of the amyloid beta (Aβ) and tau proteins. Aggregation and misfolding of Aβ and tau proteins are believed to arise from post-translational modification processes like phosphorylation, truncation, racemization, isomerization and pyroglutamylation. Defective degradation and clearance of misfolded Aβ as well as inflammation per se are crucial players in the pathology of AD. Blood-brain barrier (BBB) dysfunction causes Aβ accumulation in the brain and this occurs early in the pathophysiology of AD. More recently, a plethora of evidence emerged that links metabolic dysfunctions such as obesity, Type 2 Diabetes (T2D), and dyslipidemia with the pathophysiology of AD. We hypothesized that adding another risk factor, T2D, in addition to pyroglutamylation (hQC) of Aβ might induce a more severe AD pathology and that astaxanthin (ASX) supplementation might confer neuroprotective effects and help to ameliorate the pathophysiological manifestations associated with AD. Questions addressed: To test our hypothesis in vitro, we investigated the Aβ clearance ability of ASX in the presence of exogenous Aβ using primary porcine brain capillary endothelial cells (pBCECs) and its anti-inflammatory potentials in LPS stimulated- organotypic hippocampal slice culture (OHSC). For further validation in vivo, we used male and female transgenic AD mice, APPxhQC, expressing human APP751 with the Swedish and the London mutation and human glutaminyl cyclase (hQC) enzyme and their non-transgenic (NTG) littermate. Mice in the control groups were fed 10% kJ fat, 7% sucrose. T2D model groups were fed High-fat Diet (HFD) containing 95% (60KJ% Fat) + 5 % Maltodextrin Placebo diet with 3 doses of 40mg/kg streptozocin injection while the intervention groups were given HFD containing 95% (60KJ% Fat) + 5% NOVASTA alongside 3 doses of 40mg/kg streptozocin injection for 13 weeks starting from 11-12 months of age. We investigated the effect of T2D mimicking diet on glycemic indices, Aβ metabolism, cognitive function and nutrient-sensing pathways (autophagy, insulin, MAPKinase and mTORC1 signalling). Genes involved in lipid biogenesis and markers of nutrient-sensing pathways were evaluated at protein and mRNA levels. Expressions of lipid and liver function parameters were assessed using ELISA-based assays. Deposition of soluble and insoluble Aβ isoforms in brains were determined using ELISA, MSD-based assays and histological staining. Hippocampal-dependent cognitive impairment was assessed using the Morris Water Maze (MWM). Results: ASX enhances clearance of misfolded proteins, promotes autophagy, and alters the Aβ processing pathway in vitro. T2D mimicking diet caused a progressive shift from soluble to insoluble Aβ pools in APPxhQC male mice. The increased deposition of soluble and insoluble pGlu-3 Aβ42 was more pronounced in APPxhQC female mice. T2D mimicking diet impaired memory function in APPxhQC T2D model female and NTG male mice. The T2D phenotype was more pronounced in T2D model NTG female mice. ASX supplementation reduced Aβ deposition and might be a hQC inhibitor. ASX supplementation ameliorated T2D-induced memory dysfunction in male T2D model NTG mice possibly by enhancing NTG Aβ clearance and degradation via autophagy and improving nutrient signalling (autophagy, insulin and inflammatory signaling pathways) in both brain and liver. Conclusion: We demonstrated ASX's potential in addressing AD-related blood-brain barrier challenges and inflammation in vitro. Furthermore, we showed that T2D poses an additional risk to AD pathophysiology and could lead to cognitive impairment induced by metabolic dysfunction. In addition, T2D influences Aβ metabolism and cognitive impairment with sex and genotype playing different roles. ASX might inhibit hQC but supplementation alone is not effective in presence of comorbidities and in lat