# Impact of apolipoprotein E isoforms on brain lipoproteins

> **NIH NIH R03** · BATTELLE PACIFIC NORTHWEST LABORATORIES · 2021 · $192,621

## Abstract

Project Summary/Abstract
 Cerebrovascular dysfunction leads to the deposition of amyloid plaques and neurofibrillary tangles in the brain
which underlie the development of Alzheimer’s disease (AD); an epidemic that affects more than five million
Americans. Brain lipoproteins (BLps) are lipid-protein complexes that are essential for maintaining brain lipid
homeostasis and protecting against neurodegeneration. Unfortunately, detailed studies on BLps have been
severely limited as their abundance in cerebrospinal fluid (CSF) is 200-fold less than lipoprotein levels in plasma.
It is known that BLps are produced independently in the central nervous system and they are thought to emulate
compositional and functional features of plasma high-density lipoproteins (HDL). The dominant organizing
scaffold on BLps is APOE which has three isoforms—APOE2, APOE3, and APOE4 that differ by cysteine-
arginine exchanges at residues 112 and 158. Carriers of APOE4 are at an elevated risk for development and
increased severity of AD. We hypothesize that, similar to APOA1 on HDL, APOE acts as a regulatory scaffold
on BLps and conformational differences in APOE isoforms result in altered speciation and particle function that
underlies the APOE isoform-specific impact on development of AD. We have developed a highly-sensitive
lipoprotein profiling technology unique to our laboratory to overcome the BLp abundance hurdle in CSF. Our
preliminary work shows that, like plasma HDL, BLps are a widely diverse population of unique particles with
distinct protein complements. Moreover, we have developed a protocol for using cryo-electron microscopy to
visualize lipid-bound apolipoproteins in unprecedented detail. We will leverage these technologies to 1)
determine the impact of APOE isoform on the composition and distribution of BLps and 2) determine the
molecular basis of how APOE isoforms structurally regulate BLps. Importantly, we will directly relate differences
to clinical AD endpoints in the same individuals. This work will significantly accelerate our understanding of BLp
composition, structure, and function and the specific role of APOE in the development of AD.

## Key facts

- **NIH application ID:** 10108736
- **Project number:** 1R03AG070480-01
- **Recipient organization:** BATTELLE PACIFIC NORTHWEST LABORATORIES
- **Principal Investigator:** John Melchior
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $192,621
- **Award type:** 1
- **Project period:** 2021-04-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10108736

## Citation

> US National Institutes of Health, RePORTER application 10108736, Impact of apolipoprotein E isoforms on brain lipoproteins (1R03AG070480-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10108736. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*