# Regulation of Microglial Activation State by a Lipid Transporter

> **NIH NIH R01** · UNIVERSITY OF KENTUCKY · 2024 · $374,285

## Abstract

Abstract
Functional genome wide association studies have indicated that dysregulated microglia activation
is a major contributing factor for neurodegeneration and cognitive decline in Alzheimer's disease
(AD). Thus, regulating the microglia activation state could have profound therapeutic potential for
AD. However, the underlying mechanisms by which microglia transition between different states
during normal and disease conditions are largely unknown. S1P-signaling has been implicated to
play important roles in AD. Yet the function of S1P in AD is not clear due to conflicting reports.
On one hand, the level of S1P is reduced in postmortem AD patient brains, suggesting a
protective role of S1P. On the other hand, there are also reports indicating that S1P might play
the opposite. Although has been tested in Aβ-related AD mouse models, the role of FTY720 in
tau pathology is elusive. Further, FTY720 can have different function depending on the cellular
context and treatment procedure, which makes interpretation of S1P's role challenging. Thus, the
function of S1P-signaling in AD is more complex than assumed and demands further investigation
Our preliminary studies suggest that Spinster homolog 2 (Spns2), an S1P transporter, critically
modulates microglial transition from inflammatory to anti-inflammatory states when treated with
Aβ peptide. This data is interesting in that it reveals microglia states could be regulated through
Spns2 and/or S1P. Since microglia form the first and major line of immune defense in the central
nervous system, we will mainly investigate the function of Spns2 on microglia activation in this
application. The role of astrocytes, the other major glial cell type, and other S1P transporters such
as ABCA1, will also be evaluated. Our goal is to define the function and underlying mechanism
of Spns2 in microglial responses in AD. Our goal is to define the function and underlying
mechanism of Spns2 in microglial responses in AD. Our overarching hypothesis is that Spns2
contributes to AD pathogenesis by promoting microglial pro-inflammatory activation induced by
AD-related stimuli. We will Test that (1) Spns2 enhances pro-inflammatory responses in microglia
induced by AD-related stimuli, (2) Spns2/S1P promotes NFκB and p38 MAPK pro-inflammatory
signaling induced by Aβ and tau in microglia, and (3) Spns2 deficiency ameliorates AD-related
phenotypes in murine AD models. By focusing on the S1P transporter Spns2, this proposal holds
a unique premise to reveal novel aspects of S1P-signaling in AD pathogenesis.

## Key facts

- **NIH application ID:** 10765729
- **Project number:** 5R01AG064234-05
- **Recipient organization:** UNIVERSITY OF KENTUCKY
- **Principal Investigator:** Erhard Bieberich
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $374,285
- **Award type:** 5
- **Project period:** 2020-03-01 → 2025-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10765729

## Citation

> US National Institutes of Health, RePORTER application 10765729, Regulation of Microglial Activation State by a Lipid Transporter (5R01AG064234-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10765729. Licensed CC0.

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