# Investigating the role of apolipoprotein E in brain ferroptosis sensitivity

> **NIH NIH R21** · BROAD INSTITUTE, INC. · 2020 · $425,000

## Abstract

Aging-related neurological diseases impact millions people worldwide, and this number is expected to increase
drastically as the global average age continues to increase. While the need to develop new neuroprotective
therapeutics has never been higher, our current efforts rely on only a partial understanding of the molecular,
cellular, and circuit mechanism that drive changes in the aging brain. One such change is increased oxidative
stress arising partially from the brain’s high metabolic needs and exacerbated by brain enrichment of oxidation-catalyzing transition metals and incorporation of peroxidation-sensitive polyunsaturated fatty acid (PUFA)
species into phospholipid membranes. Accumulation of peroxidized lipids results in membrane damage and
ferroptosis, an iron-dependent, non-apoptotic mode of cell death. Our preliminary data suggest that neurons,
astrocytes, and microglia are susceptible to ferroptosis, whereas oligodendrocytes are resistant. However, the
mechanisms regulating differential susceptibility to ferroptosis in these cell types remain unknown.
One possible connection between ferroptosis and neurodegeneration is apolipoprotein E (apoE), the primary
lipid and cholesterol transport protein of the central nervous system (CNS). APOE gene variants modulate the
probability of developing neurodegenerative disease, with each apoE4 allele conferring an approximately 2-fold
increase in risk for late-onset Alzheimer’s disease compared the more common apoE3 allele. In contrast, the
apoE2 variant is enriched in cognitively-intact elders. While many characteristics differentiate apoE4 from the
other isoforms, including decreased protein stability and altered lipid transport, no one mechanism is considered
responsible for increased risk of neurodegeneration in apoE4 carriers. Recent work shows that apoE mediates
transfer of peroxidation-sensitive fatty acids from neurons to astrocytes during periods of enhanced neuronal
activity, suggesting that deficient capacity for lipid transport could lead to accumulation of these potentially toxic
species in neurons. Interestingly, our preliminary data suggest that astrocytes expressing apoE3 may be
protected against some forms of ferroptosis compared to apoE knockout astrocytes, but that this susceptibility
can be rescued by exogenous application of plasma high density lipoproteins (HDL).
We propose to validate our initial findings using primary culture of CNS cells. Because interactions among cell
types in the brain are critical for modeling of brain lipid metabolism, we will use organotypic slice culture to
investigate the impact of apoE isoform on ferroptosis sensitivity. To characterize how isoform-dependent
differences in apoE-lipid interactions impact CNS ferroptosis sensitivity, we will complex apoE to purified plasma
HDL and test how these particles impact ferroptosis sensitivity. Lastly, we will identify the lipid species conferring
resistance to ferroptosis in our preliminary data by constru...

## Key facts

- **NIH application ID:** 10043073
- **Project number:** 1R21AG068769-01
- **Recipient organization:** BROAD INSTITUTE, INC.
- **Principal Investigator:** Sarah EV Richards
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $425,000
- **Award type:** 1
- **Project period:** 2020-09-11 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10043073

## Citation

> US National Institutes of Health, RePORTER application 10043073, Investigating the role of apolipoprotein E in brain ferroptosis sensitivity (1R21AG068769-01). Retrieved via AI Analytics 2026-06-05 from https://api.ai-analytics.org/grant/nih/10043073. Licensed CC0.

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