Iron toxicity potentiates cell-type specific amyloid beta proteotoxicity in C. elegans via altered energy homeostasis.

Alzheimer's disease (AD) is a devastating neurodegenerative disorder characterized by memory loss and a decline in cognitive function. Hallmarks of AD include an age-dependent accumulation of toxic amyloid beta (Aβ) 42 in the brain, energy dyshomeostasis caused by mitochondrial dysfunction, and iron overload. However, the role of iron overload and mitochondrial dysfunction in AD pathology is unknown and their precise relationship with Aβ 42 toxicity in AD pathology is unclear. C. elegans provide a powerful model system to untangle and clarify these relationships. In this study, we quantify the temperature-dependence of iron toxicity (16, 20 and 25°C) in neurons and muscle of C. elegans that overexpress Aβ 42. We found that Aβ 42, regardless of the cell-type expression, caused accelerated paralysis compared to age-matched WT worms with the greatest degree of paralysis observed at an elevated temperature (25°C). Moreover, the combination of iron toxicity and Aβ 42 results in an enhanced paralytic phenotype at 16°C. Thus, iron exposure potentiates Aβ toxicity observed at low temperatures. Iron toxicity stimulated both maximum (State 3) and leak (State 4) respiration in WT and Aβ 42 worms. Aβ 42 worms also exhibited increased leak respiration at baseline that was further exacerbated by iron toxicity. Iron burden and sensitivity increased Aβ 42 peptide toxicity. Aβ 42 worms exhibited reduced levels of Ca, Zn, Mn, and K. Overall, our results suggest that iron potentiates Aβ toxicity at low temperature and enhances Aβ peptide mediated mitochondrial bioenergetic dysfunction in C. elegans.