# Administrative Supplement: Zinc-APOE4 interaction and toxicity in the central nervous system (CNS)

> **NIH NIH R01** · STATE UNIVERSITY NEW YORK STONY BROOK · 2024 · $395,387

## Abstract

Summary: Zinc-APOE4 interaction and toxicity in the central nervous system (CNS)
Alzheimer’s disease (AD) stands as the most widespread form of dementia globally, and its prevalence is on a
steep ascent with the increasing aging population. Among the genetic risk factors contributing to AD, the
Apolipoprotein E (ApoE) gene, particularly its 4 allele, occupies a central role, accounting for over half of all AD
cases. Meanwhile, the emerging concept of zinc (Zn) dyshomeostasis has gained prominence, owing to its
intriguing association with AD pathogenesis. Zinc, an essential trace element in human biology, assumes a
paradoxical role as it can be neurotoxic at elevated concentrations while also modulating crucial cellular
processes. Notably, multiple studies suggest that Zn can instigate the aggregation of Aβ protein, the primary
constituent of senile plaques frequently observed in AD brains. In neurological conditions marked by apoptotic
neuronal death, chelatable Zn tends to accumulate within neurons, either preceding or coinciding with
degeneration. Given the substantial evidence for apoptotic neuronal demise in AD, the involvement of Zn in this
process warrants thorough exploration. Notably, clinical trials have shown promise in using PBT2, a copper/zinc
ionophore, for AD treatment. Moreover, recent insights indicate that interactions between brain metal ions and
Apolipoprotein E4 (APOE4), the most potent genetic risk factor for AD, may constitute one of the mechanisms
driving neurodegeneration. APOE exhibits isoform-dependent affinity for Zn, with ApoE2 > ApoE3 > APOE4.
This interaction influences Aβ aggregation, with APOE2 mitigating Zn-induced Aβ precipitation, while APOE4
carriers exhibit a greater abundance of neurotoxic fragments. Dysregulated Zn levels in AD patients could
potentially exacerbate neurodegeneration by affecting ApoE expression, particularly APOE4. However, the
precise alterations in Zn concentration and the effects of Zn overload or deficiency in AD across patients, animal
models, and cell lines remain areas of debate. To address these crucial questions, this study unfolds in two main
aims: Firstly, to investigate the interactions between Zn and APOE4 and their potential impact, utilizing molecular
docking, spectroscopy, and Surface Plasmon Resonance (SPR) to comprehend how Zn influences APOE4
conformation, and exploring the role of metal ion chelators like EDTA. Secondly, to examine the toxicity of Zn-
APOE4 interactions across various brain cell types, encompassing cell viability, cytotoxicity, glial cell activation,
inflammation, mitochondrial dysfunction, and caspase activation, aiming to elucidate their contribution to AD
pathology. These investigations may offer novel insights into Zn’s role and potential therapeutic avenues for AD
by targeting Zn dyshomeostasis.

## Key facts

- **NIH application ID:** 10933687
- **Project number:** 3R01DK129493-02S2
- **Recipient organization:** STATE UNIVERSITY NEW YORK STONY BROOK
- **Principal Investigator:** Yi-Xian Qin
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $395,387
- **Award type:** 3
- **Project period:** 2022-02-03 → 2027-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10933687

## Citation

> US National Institutes of Health, RePORTER application 10933687, Administrative Supplement: Zinc-APOE4 interaction and toxicity in the central nervous system (CNS) (3R01DK129493-02S2). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10933687. Licensed CC0.

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