# Role of TTYH1 in mobilizing lipids and ApoE in glia: Implications for brain aging and neurodegeneration

> **NIH NIH R01** · RUTGERS THE STATE UNIV OF NJ NEWARK · 2024 · $343,438

## Abstract

PROJECT SUMMARY
Lipids occupy over half of the dry weight of human brain. Brain cells rely on lipid metabolism to meet energy
needs, perform signaling functions, and regulate membrane integrity and dynamics. Alterations in lipidomic
profiles have been observed in aging brains and in neurodegenerative diseases such as Alzheimer’s disease
(AD) and related dementia (ADRD), suggesting that reprogramed lipid metabolic pathways may be involved in
disease pathogenesis. Notably, APOE and other lipid metabolism related genes have been associated with
late-onset AD. Despite these observations, how aberrant metabolism of certain lipid classes mechanistically
contribute to brain cell malfunction remains largely undefined. We sought to identify molecular pathways
pertinent to brain lipid metabolism by utilizing approaches that combine molecular genetics and omics. Our
transcriptomic analysis identified Tweety Homolog 1 (TTYH1) whose expression in human brain highly
correlates with APOE. Such correlation between TTYH1 and APOE is lost in astrocytes of AD patients. Using
human primary astrocyte and Drosophila model, we found that TTYH1 and its fly ortholog are required for
ApoE secretion. Cell biology experiments further suggest that TTYH1 and its ortholog are required for
autophagy and lipid droplet (LD) breakdown in glia. Lipidomic analyses of drosophila brains and human
astrocytes deficient in TTYH1 orthologs revealed altered phospholipid abundances indicative of elevated
cytosolic phospholipase A2 (cPLA2) activity. These preliminary findings inform our overarching hypothesis that
TTYH1 is essential for a novel pathway connecting glial LD breakdown to lipoprotein secretion. In aim 1, we
will test if cPLA2-activating ceramide metabolites regulates LD breakdown in glia, and define the function of
TTYH1 in this process. Aim 2 will elucidate the mechanism of how TTYH1 regulates lipoprotein secretion in
astrocytes. The significance of TTYH1-mediated lipid mobilization in brain aging and ADRD will be evaluated in
Aim 3. We will assess the functional outcomes of perturbing TTYH1 ortholog in drosophila models of aging and
ADRD. We will also examine the role of glial TTYH1 on neuronal homeostasis using coculture of brain cells
derived from Ttyh1 conditional knockout mice. In summary, the project will integrate molecular genetics and
lipidomics to illuminate a novel lipid metabolic pathway that hinges on TTYH1 in brain aging and ADRD.
Findings from this project will aid in defining whether TTYH1 and its associated molecular players can serve as
therapeutic targets for treating neurodegeneration.

## Key facts

- **NIH application ID:** 10837109
- **Project number:** 5R01AG081379-02
- **Recipient organization:** RUTGERS THE STATE UNIV OF NJ NEWARK
- **Principal Investigator:** Ching-On Wong
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $343,438
- **Award type:** 5
- **Project period:** 2023-05-15 → 2028-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10837109

## Citation

> US National Institutes of Health, RePORTER application 10837109, Role of TTYH1 in mobilizing lipids and ApoE in glia: Implications for brain aging and neurodegeneration (5R01AG081379-02). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10837109. Licensed CC0.

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