Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
Sunkara, S.
Understanding Iron Dynamics in Aging and Alzheimer's Disease:
Insights from Post-Mortem Analysis and Brain Slice Cultures
PhD-Studium (Doctor of Philosophy); Humanmedizin; [ Dissertation ] Medizinische Universität Graz; 2023. pp.
- Autor*innen der Med Uni Graz:
- Sunkara Sowmya
- Betreuer*innen:
- Leitinger Gerd
- Patz Silke
- Sattler Wolfgang
- Altmetrics:
- Abstract:
- Iron accumulation has been implicated in ageing and neurodegenerative diseases, including Alzheimer's disease (AD). This study aimed to investigate the impact of iron overload on different cell types in ageing and AD conditions. We quantified the iron stored in its storage protein - ferritin using analytical electron microscopy and the total iron using Inductively Coupled Plasma Mass Spectrometry (ICP-MS) and quantitative Magnetic resonance Imaging(qMRI) in the post-mortem human brains. While we confirm earlier studies that show a higher concentration of ferritin in oligodendrocytes than in neurons, we described for the first time that the ferritin concentration increased in neurons compared to glial cells, when the total ferritin levels increased in the brain. These findings contribute to understanding iron distribution and storage patterns in aged individuals and their implications for neurodegenerative diseases like AD. We proceeded to investigate the role of iron in AD. We established a suitable organotypic brain slice culture (OBSC) model to study AD pathology. Brain specimens from different sources were evaluated. The final working model of OBSC was established from the hippocampus region dissected from the post-mortem human brain supported by porcine brains. To study the interplay between iron and amyloid beta, we used ferric citrate (Fe-Citrate) to induce iron-overload condition and synthetic amyloid beta 1-42 (Aβ) peptides to induce aggregates of Aβ fibrils. We reveal a temperature-dependent influence of Fe-Citrate on the aggregation of Aβ peptides into mature fibrillary networks using negative staining. We investigated the toxic effects of iron overload on Aβ aggregation in hippocampal OBSC using live/dead cytotoxicity assay and LDH assay. For the first time, we described in ex vivo human hippocampal slices that the neurons but not glial cells internalized the Aβ. Unlike glial cells, neurons showed increased cell death when treated with Fe-Citrate, Aβ and highest neuronal loss when treated with both. Our research findings describe for the first time, that iron toxicity is biased towards neurons when combined with Aβ, indicating that iron exacerbates the toxic effects of Aβ. While many studies primarily focus on Aβ-induced neuronal loss without taking into consideration the role of iron, our investigation sheds light on the ex vivo effects of Fe-Citrate on Aβ in the human hippocampus and is supported by the findings in the porcine hippocampus. Our findings highlight the impact of iron on the formation of mature Aβ aggregates, leading to toxicity and neuronal loss.