# Neuronal Protective Apolipoprotein E2-mediated endocytic and exocytic pathways

> **NIH NIH RF1** · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · 2020 · $249,884

## Abstract

ABSTRACT
Apolipoprotein E (ApoE) genotype, the primary carrier of cholesterol within the brain, is an important
determinant of an individual's risk for developing Alzheimer's disease (AD). While the ε2 allele (ApoE2)
appears to be protective, ApoE4 increases the risk for the disease. Growing evidence, including our findings
within this application, argue that ApoE genotype affects the endosomal and exosomal pathways. In young
ApoE2 mice, our preliminary studies have shown that neuronal early endosomes are reduced in size and
number while a greater number of exosomes are seen in the brain extracellular space as compared to mice
expressing the human ApoE3 allele, the neutral-risk allele in humans, or mice expressing the pathogenic
ApoE4 allele, which leads to abnormally enlarged early endosomes and lower levels of exosomes in older
mice. We propose that exosomes, secreted vesicles generated within endosomal compartments, help clear
endosomal vesicular content from the endocytic pathway, thus contributing to the preservation of neuronal
endosomal function during aging. Additionally, we hypothesize that the facile movement of cargo through the
endocytic pathway in ApoE2 carriers contributes to efficient lysosomal function. This combination of endosomal
and exosomal changes driven by ApoE2 suggests interrelated, and potentially additive, neuroprotective cellular
processes. We propose to test our hypothesis that expression of the ApoE2 allele results in protective changes
within the endosomal and exosomal pathways by examining humanized ApoE mouse brain at various ages as
well as ApoE genotyped human brain tissue (Aim 1). In brain-derived endosomes and exosomes we will
examine the lipidome and proteome and in exosomes, RNAs to identify molecular alterations that mediate
protective ApoE2 endosomal and exosomal functions. To tie ApoE2 cell biology to brain function we focus on
the olfactory system. Several recent studies, including both mouse and human data in part from our group,
demonstrate that olfactory sensory physiology and perception may be especially sensitive biomarkers of ApoE
genotype. For example, ApoE4 carriers have impaired odor identification (humans), impaired odor memory and
olfactory system hyperexcitability (mice). In Aim 2, we will examine both olfactory sensory physiology and
behavior to test the hypothesis that the ApoE2 isoform modulates olfactory function and can rescue ApoE4
deficits. Finally, in preliminary studies we have shown that a high fat/cholesterol diet causes neuronal
endosomal pathway pathology in wild-type mice. In Aim 3, we will test our hypothesis that ApoE2-induced
efficiencies in the endosomal and exosomal pathways protect from dietary lipid-induced endosomal pathway
abnormalities. The overall objectives of our study are to characterize interconnected cellular pathways that we
propose are protective in individuals expressing ApoE2 and to determine whether maintaining efficient
endosomal and exosomal function throu...

## Key facts

- **NIH application ID:** 10148376
- **Project number:** 3RF1AG057517-01S2
- **Recipient organization:** NEW YORK UNIVERSITY SCHOOL OF MEDICINE
- **Principal Investigator:** EFRAT LEVY
- **Activity code:** RF1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $249,884
- **Award type:** 3
- **Project period:** 2017-09-15 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10148376

## Citation

> US National Institutes of Health, RePORTER application 10148376, Neuronal Protective Apolipoprotein E2-mediated endocytic and exocytic pathways (3RF1AG057517-01S2). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10148376. Licensed CC0.

---

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