Excess iron may accelerate amyloid beta accumulation in the brains of older mice.

Abstract

Aging is a natural physiological process that may be accompanied by pathological changes, particularly in the brain. Iron is an essential trace element supporting various physiological functions and maintaining cellular homeostasis. However, iron levels tend to increase in certain brain regions of older adults and are associated with the development of neurodegenerative diseases. Despite this association, the causal relationship between aging, iron accumulation, and neurodegenerative diseases remains unknown. This study aimed to elucidate the potential contribution of systemic iron overload (IO) to brain pathology during aging. An IO model was established by intraperitoneal iron dextran (0.5 g/kg), 5 days/week for 4 weeks into C57BL/6 mice. Animals were divided into control and IO groups and further categorized into younger and older mice. No parenchymal iron accumulation was observed in any group; however, ferritin expression increased with IO and showed as plaques in older mice regardless of IO. Amyloid beta (Aβ) aggregation was observed in the entorhinal cortex and hippocampus, with higher burden in the older IO group. Ferritin plaques localized to the same regions as Aβ aggregation, and both showed a marked increase in older IO mice. The hippocampal Aβ 42/40 ratio was also increased in this group. Additionally, excessive iron was associated with reduced exploratory activity and showed trends toward impaired spatial working memory in older mice. These findings suggest that while aging is not pathological, IO may accelerate Aβ pathology during aging, although the presence of such pathology does not necessarily indicate neurodegeneration or cognitive impairment.