Characterizing the Role of Heme in Alzheimer’s Disease Pathogenesis




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In humans, heme accounts for 97% of functional iron. With a porphyrin ring and an iron ion, heme possesses structural and chemical features fitting for electron transfer, oxidation/reduction, and interaction with oxygen. Three oxidative phosphorylation (OXPHOS) complexes, II, III, and IV, require heme for proper functioning. Cells that require high levels of adenosine triphosphate (ATP) and OXPHOS require elevated levels of heme. Heme also serves as a powerful antioxidant for cells because it can be degraded to biliverdin and reduced to bilirubin. The reduction of biliverdin to bilirubin helps relieve reactive oxygen species (ROS) in cells. Neuronal cells are known to be high-energy demanding cells that depend on mitochondrial respiration to function. Specifically, in neurodegenerative diseases such as Alzheimer’s Disease (AD), mitochondrial dysfunction is one of the key characteristics associated with the progression of this disease. Oxidative stress has also been implicated in the pathogenesis of AD. Due to the role of heme in both of these cellular functions, it is important to understand how heme contributes to neuronal function and how it may play a pivotal role in developing this neurodegenerative disease. The objective of this research is to dissect the role of heme in the pathogenesis of AD. Utilizing immunocytochemistry and Western blot techniques, I have depicted the importance of heme in neuronal development. Heme uptake, synthesis, and degradation are significantly increased in developing and differentiating neurons. This increase in heme flux coincides with an increase in mitochondrial proteins. Using the APPPS1 mouse model and microarray expression data of human patients, I detected specific heme-related enzymes that are downregulated in AD. These alterations can lead to a decrease in the availability of heme for cellular functions. The decrease in heme availability can lead to disturbed mitochondrial function and an increase in oxidative stress. Furthermore, to glean whether heme flux alterations are early and potentially initiating causes of AD, I utilized patient-derived neurons generated from human-induced pluripotent stem cells (iPSCs). These studies revealed a distinct role of heme in the development of familial (FAD) and sporadic AD (SAD). SAD neurons have downregulated heme synthetic and degradation enzymes, while FAD neurons only had a slight yet significant reduction in the biliverdin reductase B (BLVRB) enzyme involved in heme degradation. Moreover, analysis of the tricarboxylic acid (TCA) cycle enzymes and intermediates revealed a significant alteration in enzymes and intermediates within both SAD and FAD neurons relative to gender-matched controls. This study revealed that although heme flux alterations are likely an early event in SAD pathogenesis, perturbations in the TCA cycle are probably a common characteristic of both SAD and FAD.



Biology, Molecular, Biology, Cell