Abstract 15543: Increased Local Hepcidin Expression With Subsequent Degradation Of Ferroportin-1 is Associated With Iron Accumulation in the Aged Brain

Abstract

Background: Age is a major risk factor for a number of neurodegenerative disorders, including Parkinson’s and Alzheimer’s disease. Several studies have shown that neurodegenerative disorders are sometimes associated with iron accumulation in the brain. Iron is an essential trace metal, however, excess iron can cause cellular damage due to increased oxidative stress and thus promote aging, yet how and why iron accumulates in the aged brain is unclear. The goal of this study is to delineate the mechanism of iron accumulation in the brain with aging. Results: We assessed the levels of iron in various tissues of aged mice (defined as 22 months old) vs young mice (defined as 4 months old). We found that non-heme iron was preferentially increased in the brain tissue of aged mice, while the levels were unaltered in other tissues. This was associated with increased ferritin (iron storage protein) levels in the brain, consistent with iron accumulation. To study the mechanism, we measured the mRNA levels of various proteins involved in iron homeostasis, and determined that the levels of hepcidin (HAMP) and tranferrin receptor-2 were increased in the brains, but not in the livers, of aged mice. HAMP is generally produced in the liver and functions to reduce intestinal iron uptake through degradation of basolateral iron exporter ferroportin-1 (FPN1), thus reducing systemic iron levels. However, HAMP is also detected in other tissues, such as the brain and the heart, where its function is less clear. To determine whether the increase in HAMP in the brain affects iron homeostasis, we measured the levels of FPN1 in the brain and showed that while its mRNA level was not altered, the protein level of FPN1 was significantly reduced in aged mice. Thus, the increase in HAMP in aged mice was associated with a reduction in FPN1 levels and iron accumulation in the brain, likely through reduced iron export from neurons and glial cells. Conclusions: Our results demonstrate that iron levels are significantly increased in the brain with aging. This increase is due to higher levels of HAMP protein, with subsequent degradation of iron exporter FPN1 and cellular iron accumulation secondary to defective export. Thus, targeting HAMP may lead to novel therapies for age-related neurodegenerative disorders.