Abstract
Disclosure: V. Ryu: None. R. Witztum: None. A. Gumerova: None. S.L. Sims: None. O. Moldavski: None. F. Korkmaz: None. M. Planoutene: None. M. Levy: None. P. Na-Phatthalung: None. G. Pevnev: None. J. Ryu: None. B. Tumoglu: None. O. Barak: None. T. Frolinger: None. T. Yuen: None. M. Zaidi: None. Y. Ginzburg: None. Iron homeostasis ensures adequate iron for important physiological processes and its excessive accumulation can lead to manifestation of various neurodegenerative diseases including Alzheimer’s disease (AD). The hormone erythroferrone (ERFE), produced by erythroblasts in the marrow and the spleen, is a negative regulator of hepcidin in hepatocytes that leads to increased iron mobilization from stores and dietary iron absorption. Notably, ERFE/hepcidin pathway has been demonstrated to play an important role in iron metabolism in non-erythropoietic tissues. Considering the central role of astrocytic hepcidin in iron homeostasis, it is not surprising that ERFE has emerged as a promising novel target for iron regulation in the brain. Alternatively, chronic effects of brain ERFE per se may play an important role in the genesis and progression of AD. To purposefully delineate ERFE as a regulatory node in AD, we employed RNAscope to map Erfe single transcript expression in murine brains. Here, we report the presence of central ERFE expressing nodes distributed within 65 of healthy and 82 of AD brain nuclei, sub-nuclei and regions. We demonstrate for the first time that overall brain Erfe transcript density is greater in 3xTg mouse model of AD comparing to healthy counterparts suggesting that elevated ERFE may contribute to underlying AD. We created the most comprehensive atlas of ERFE expression in the brains of normal and 3xTg mice. In concert with RNAscope findings, qPCR analyses have revealed dramatic alterations in the expression of three iron mediators. Namely, (1) ferroportin1 (Fpn1)—the primary exporter of iron from cells—was significantly greater in the brain, particularly, in the hippocampus of AD mice; (2) transferrin receptor 1 (Tfr1)—uptake regulator of iron-loaded transferrin—was significantly greater in the brain, and (3) poly(rC)-binding protein 2 (PCBP2)—an intracellular iron chaperone—was significantly greater in the cortex and hippocampus. TFR1 protein concentration was also increased in the western blot only in the cortex with no change in FPN1 was identified. This suggests an appreciated role of hippocampal and cortical iron in modulating AD progression under conditions of chronically elevated ERFE in the brain, in general, and in the hippocampus and cortex, specifically. Collectively, our results show persuasive evidence of distributed ERFE nodes with coordinated or multiple redundant control of iron homeostasis in the brain. Although the extent of elevated ERFE and/or iron contribution to aetiology of AD is far from complete, we hope this study will provide a resource to better understand brain ERFE as a new potential therapeutic target for neurodegenerative diseases. Presentation: Sunday, July 13, 2025