# Enhanced APOE2 Expression into Brain for Therapeutic Strategy for Alzheimer's Disease

> **NIH NIH R01** · NORTH DAKOTA STATE UNIVERSITY · 2024 · $525,712

## Abstract

SUMMARY/ABSTRACT:
Alzheimer’s disease (AD) is a progressive neurodegenerative disease that has emerged as the most prevalent
form of late-life dementia in humans. The accumulation, aggregation, and deposition of amyloid-β (Aβ) in the
brain are central events in AD pathogenesis. Despite intense effort, an effective therapy for AD has yet to be
established. While multiple genetic and environmental factors are involved in AD pathogenesis, the ε4 allele of
the APOE gene encoding apolipoprotein E (APOE) is the strongest genetic risk factor for late-onset AD among
the three human APOE genotypes (ε2, ε3, ε4). In humans, Aβ deposition is more pronounced in APOE4 carriers
compared with non-carriers in both AD patients and aged healthy individuals. APOE plays a critical role in
maintaining synaptic plasticity and neuronal function by controlling lipid homeostasis, with the APOE2 allele
having a superior function. The ε2 allelic variant has been found to be more prevalent among centenarians and
associated with decreased susceptibility to AD. Studies on the role of the APOE2 in relation to AD suggest that
APOE2 is neuroprotective and positively associated with cognitive functions in aging. Therefore, increasing
APOE2 levels in the brain is predicted to be an effective therapeutic strategy for AD. Development of successful
strategies for treating these disorders is limited due to the protective function of blood brain barrier (BBB). Gene
therapy possesses a broad potential for the treatment of numerous neurological diseases, including AD.
However, the major challenge in the field of gene therapy is the design of safe non-viral vectors that can cross
the BBB. The transferrin (Tf) receptors are present on the surface of brain endothelial cells. The lipid
nanoparticles can be surface modified with Tf protein for targeting the brain endothelial receptors and conjugated
to brain specific cell penetrating peptide (CPP) for improving their internalization into brain by overcoming
receptor saturation. Therefore, we propose to design near neutral, PEGylated liposomal nanoparticles
encapsulating gene and modifying the surface of nanoparticles with Tf and CPP. Furthermore, the transfection
properties of chitosan will be utilized for improving the transfection of gene by facilitating endosomal escape via
the proton-sponge mechanism inside the cells. The long-term goal of the proposed research is to design a non-
viral gene delivery carrier for efficient delivery of plasmid DNA encoding APOE2 (pAPOE2) to brain for prevention
and treatment of AD. We propose three specific aims to accomplish the long-term goal of the proposed research:
Aim 1. Synthesize and characterize liposomal nanoparticles loaded with chitosan-pAPOE2 polyplexes:
The brain specific CPP-liposomes will be synthesized using thin film hydration technique followed by insertion of
Tf coupled micelles using post-insertion technique. We propose to use five BBB specific CPPs: (i) CGN (d-
CGNHPHLAKYNGT); (ii) RDP ...

## Key facts

- **NIH application ID:** 10891760
- **Project number:** 4R01AG068034-02
- **Recipient organization:** NORTH DAKOTA STATE UNIVERSITY
- **Principal Investigator:** Takahisa Kanekiyo
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $525,712
- **Award type:** 4N
- **Project period:** 2021-05-15 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10891760

## Citation

> US National Institutes of Health, RePORTER application 10891760, Enhanced APOE2 Expression into Brain for Therapeutic Strategy for Alzheimer's Disease (4R01AG068034-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10891760. Licensed CC0.

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