Amyloid-β exposed astrocytes induce iron transport from endothelial cells at the blood–brain barrier by altering the ratio of apo- and holo-transferrin

Stephanie L. Baringer, Avraham S. Lukacher, Kondaiah Palsa, Hyosung Kim, Ethan S. Lippmann, Vladimir S. Spiegelman, Ian A. Simpson, James R. Connor

Research output: Contribution to journalArticlepeer-review

2 Scopus citations


Excessive brain iron accumulation is observed early in the onset of Alzheimer's disease, notably prior to widespread proteinopathy. These findings suggest that increases in brain iron levels are due to a dysregulation of the iron transport mechanism at the blood–brain barrier. Astrocytes release signals (apo- and holo-transferrin) that communicate brain iron needs to endothelial cells in order to modulate iron transport. Here we use iPSC-derived astrocytes and endothelial cells to investigate how early-disease levels of amyloid-β disrupt iron transport signals secreted by astrocytes to stimulate iron transport from endothelial cells. We demonstrate that conditioned media from astrocytes treated with amyloid-β stimulates iron transport from endothelial cells and induces changes in iron transport pathway proteins. The mechanism underlying this response begins with increased iron uptake and mitochondrial activity by the astrocytes, which in turn increases levels of apo-transferrin in the amyloid-β conditioned astrocyte media leading to increased iron transport from endothelial cells. These novel findings offer a potential explanation for the initiation of excessive iron accumulation in early stages of Alzheimer's disease. What's more, these data provide the first example of how the mechanism of iron transport regulation by apo- and holo-transferrin becomes misappropriated in disease that can lead to iron accumulation. The clinical benefit from understanding early dysregulation in brain iron transport in AD cannot be understated. If therapeutics can target this early process, they could possibly prevent the detrimental cascade that occurs with excessive iron accumulation. (Figure presented.).

Original languageEnglish (US)
Pages (from-to)248-261
Number of pages14
JournalJournal of neurochemistry
Issue number2
StatePublished - Oct 2023

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Cellular and Molecular Neuroscience

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