# Regulation of Apolipoprotein Secretion by TTYH1 and tweety in Glial Cells

> **NIH NIH R03** · RUTGERS THE STATE UNIV OF NJ NEWARK · 2020 · $156,000

## Abstract

Project Summary
Lipid transport is integral to lipid metabolism and stress response in the central nervous system. Lipoproteins
are the major intercellular lipid carrier between neurons and glia. The lipid composition, trafficking, and
metabolic fate of lipoproteins are largely dependent on the associated apolipoproteins. Disrupted function of
apolipoproteins result in neurodegenerative phenotypes in animal models of neurodegeneration. Furthermore,
allelic variation of the Apolipoprotein E (APOE) gene is the major risk factor of Alzheimer's Disease (AD). Glial
cells such as astrocytes and microglia are the major cell types that process and secret ApoE in the nervous
system. Glia also serve a protective role by mitigating neuronal oxidative stress, a common hallmark of AD and
other neurodegenerative diseases. While it is well established that apolipoproteins play critical roles in lipid
metabolism, our understanding of apolipoprotein transport in the nervous system is still limited. In addition,
whether glial cells couple oxidative stress response with apolipoprotein trafficking remains to be tested. Since
intracellular vesicular compartments are required for the trafficking of apolipoproteins, we hypothesize that
endolysosomal proteins functionally interact with ApoE in brain. By examining the expression profile of putative
endolysosomal genes, we identify Tweety Homolog 1 (TTYH1) that co-expresses with APOE in human brain.
Preliminary studies performed in mammalian cells and Drosophila mutant of tty, homolog of TTYH1, suggest
that tty and TTYH1 are required for the secretion of apolipoproteins, such as ApoD and ApoE, from glia and
regulating oxidative stress in the nervous system. tty mutant flies show shortened lifespan and locomotor
phenotypes. Our central hypothesis is that tty and TTYH1 regulate apolipoprotein trafficking to mitigate
oxidative stress in glial cells. In this proposal, we aim to address the roles of tty and TTYH1 in: 1) the secretion
of apolipoprotein from glia to circulation; and 2) mitigating glial oxidative stress via apolipoprotein secretion.
Our long-term goal is to delineate specific pathway that regulate ApoE/D processing and secretion in glial cells
and reveal new therapeutic targets for AD and related dementias.

## Key facts

- **NIH application ID:** 10085308
- **Project number:** 7R03AG063251-02
- **Recipient organization:** RUTGERS THE STATE UNIV OF NJ NEWARK
- **Principal Investigator:** Ching-On Wong
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $156,000
- **Award type:** 7
- **Project period:** 2019-06-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10085308

## Citation

> US National Institutes of Health, RePORTER application 10085308, Regulation of Apolipoprotein Secretion by TTYH1 and tweety in Glial Cells (7R03AG063251-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10085308. Licensed CC0.

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