Amyloid beta aggregation promoted by iron leads to neuronal loss in an ex vivo model of Alzheimer’s disease
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Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by amyloid beta (Aβ) plaques and neurofibrillary tangles. Despite well-established iron accumulation in the AD brain, its role in exacerbating Aβ toxicity is often overlooked in therapeutic research. We developed a 3D ex vivo organotypic brain slice cultures (OBSC) with Aβ monomers and ferric citrate to mimic Aβ deposits and iron overload to investigate the impact of excess iron on Aβ toxicity in pig and human brains. Light and electron microscopy, biochemical assays, and multiple regression modeling were employed to assess iron-mediated Aβ toxicity in neurons and glial cells.
We show that OBSC offer a close approximation of in vivo morphological and physiological properties and can retain both neurons and glial cells for extended periods, and respond to experimental manipulations. We show that iron promotes Aβ fibrillization into long fibrils, with this process further influenced by temperature. Aβ selectively accumulated in neurons, leading to their death, sparing glial cells. In contrast, Iron, though generally toxic to neurons, exhibited unspecific cytotoxicity. Notably, the combined presence of Aβ and iron synergistically increased neuronal death while reducing glial cell loss. Correlation analysis revealed that this synergic interaction enhances the toxicity of each other in a mutual fashion – Aβ directs the neuronal toxicity while iron promotes Aβ fibrillization, leading to targeted neuronal loss.
In conclusion, our findings emphasize the critical role of excess iron and Aβ in driving neuronal death in AD, underlining the importance of targeting iron accumulation along with Aβ clearance but also addressing in future AD therapies, while also supporting our OBSC model as a valuable platform for studying the same.