# Ferroportin and APP: Regulation of Iron Trafficking at the Blood-Brain Barrier

> **NIH NIH R01** · STATE UNIVERSITY OF NEW YORK AT BUFFALO · 2020 · $391,872

## Abstract

Redox active first row transition metals such as iron and copper have been implicated in the pathophysiology
of amyliodogenic diseases; these correlations are poorly understood at the level of mechanism. We also have
limited understanding of the physiologic role for which the amyloid precursor protein (APP) has been selected.
However, the fact that the APP transcript contains an iron response binding protein (IRBP) stem-loop structure
and like ferritin, APP protein synthesis directly correlates with cell iron content indicating that APP is part of the
“iron regulon.” This iron regulation of APP remains an unknown with respect to both iron metabolism and
amyloidogenesis; here we propose to test a specific premise with respect to a physiologic function of APP and
its secretase-dependent products. First, published work from our lab provides a clue as to the connection
between APP and iron metabolism. We have identified a unique function exhibited by a 22-amino acid residue
peptide element at the N-terminus of the BC helical bundle contained in the E2 domain in APP. Using
recombinant BC or a synthetic peptide (residues 327-348 within BC), we show that this sequence tethers
APP to and stabilizes ferroportin (Fpn) in the plasma membrane. Fpn is the sole mammalian iron exporter; by
stabilizing Fpn in the PM, sAPP stimulates cell iron-efflux. We have designated this species FTP for
Ferroportin Targeting Peptide. In binding to Fpn, sAPP/FTP acts as antagonist of the key regulator of Fpn
function, hepcidin (Hepc) indicating that sAPP is a key regulator of iron efflux from any mammalian cell that
expresses this amyliodogenic protein or shares an interstitial space that includes another cell type that does.
Although the effect of sAPP on Fpn plasma membrane display is now established, the molecular basis of this
activity and its physiologic function remain significant unknowns, significant because of: 1) the key role APP
and its products play in Alzheimer's disease and in cerebral amyloid angiopathy, CAA; 2) the implied role that
iron plays in this neurodegenerative disorder; and 3) the potential that FTP or its synthetic congeners may
have as (a) pharmacologic regulator of iron metabolism. The key element of this Application is our blood-brain
barrier transwell model system composed of brain capillary endothelial cells, astrocytes and neurons, i.e, the
cells of the neurovascular unit. Our premise is that: 1) iron regulates the expression of APP so as to modulate
the level of iron in the brain's abluminal space; 2) iron also modulates the processing of APP to Aß; and 3) Aß
in turn serves as an iron scavenger and by this mechanism is cytoprotective. We will test this premise by a
combination of biophysical structure-function, cell biologic and genetic approaches including the use of primary
cells cultured from strategically chosen mice KO lines. This research plan will: 1) provide novel insight into the
mechanism of the Fpn/APP interaction and its role in...

## Key facts

- **NIH application ID:** 9930666
- **Project number:** 5R01NS102337-04
- **Recipient organization:** STATE UNIVERSITY OF NEW YORK AT BUFFALO
- **Principal Investigator:** DANIEL J. KOSMAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $391,872
- **Award type:** 5
- **Project period:** 2017-08-15 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9930666

## Citation

> US National Institutes of Health, RePORTER application 9930666, Ferroportin and APP: Regulation of Iron Trafficking at the Blood-Brain Barrier (5R01NS102337-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9930666. Licensed CC0.

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