The Role of Iron in Prion Disease and Other Neurodegenerative Diseases
Figure 2
Hypothetical model of brain iron dyshomeostasis in neurodegenerative disorders.
Primary triggers of neurotoxicity include dysfunction or aggregation of the protein implicated in the pathogenesis of a specific neurodegenerative condition and other less defined factors including aging. Microglia and astrocytes respond to neuronal death and mount a protective response, which is soon overwhelmed by the accumulation of redox-active protein aggregates that induce neurotoxicity and accumulation of additional protein aggregates, increase in brain iron dyshomeostasis, and oxidative stress. These responses are inter-linked, and form a vicious cycle. Inflammatory response to neuronal death increases cytokine release that activates astrocytes and increases microglial activity and death with the release of intracellular iron. These events increase iron imbalance, redox-iron mediated protein aggregation, and significantly increase neurotoxicity. Brain iron dyshomeostasis occurs early and is one of the primary triggers of neurotoxicity if the pathogenic protein is involved in cellular iron metabolism. In other cases, iron dyshomeostasis is initiated by neuronal death, is fueled by microgliosis, activated astrocytes, and redox-active protein aggregates, and spirals when inflammation sets in, amplifying the neurotoxicity.