# Regulation of microglia in Alzheimer's Disease by Siglecs and Siglec ligands

> **NIH NIH R56** · JOHNS HOPKINS UNIVERSITY · 2020 · $785,544

## Abstract

Microglia are implicated in the initiation and progression of Alzheimer’s disease (AD), making their regulation
a therapeutic target. As positive effectors, microglia phagocytose and clear toxic proteins; as negative effectors
they release inflammatory mediators. Imbalance of microglial function is believed to contribute to AD progression.
Among microglial regulatory proteins linked to AD susceptibility are immune inhibitory members of the Siglec
family, sialic acid binding immunoglobulin-like lectins. Siglec overexpression results in increased susceptibility
to AD; depletion decreases susceptibility, supporting the hypothesis that Siglec-mediated inhibition restricts
microglial phagocytosis and exacerbates AD proteinopathy. Multiple inhibitory Siglecs are expressed on human
(and mouse) microglia. They bind to complementary ligands – sialic acid-terminated glycan chains on
glycoproteins in the local brain milieu – to trigger immune suppression. We discovered a sialoglycan ligand for
microglial inhibitory Siglecs in human cerebral cortex. We propose that this ligand is responsible for Siglec-
mediated microglial inhibition. Knowledge of the structure of this ligand, its expression and its function may
provide new opportunities for therapeutic microglial modulation. Three aims leverage the diverse expertise of
three principal investigators to test the hypothesis that Siglecs and Siglec ligands function in microglial regulation
and AD progression in vivo. We will also develop drug-like Siglec inhibitors to impact Siglec function in the brain.
Completion of these aims will help define the roles of immunomodulatory Siglecs and Siglec ligands in AD, and
may provide novel lead molecules for AD therapy.
 Aim 1: Identify microglial Siglecs and Siglec ligands in human and mouse brains. Several immune inhibitory
Siglecs are expressed on human microglia. Using expressed Siglecs as probes, we discovered a Siglec ligand
in human brain cortex and identified it as a sialylated keratan sulfate proteoglycan. The ligand appears to be
overexpressed in human AD, and mice express a similar ligand. We will characterize the expression of Siglecs
and Siglec ligands in human AD and mouse models of AD, identify the protein carrier of Siglec ligands in human
and mouse, and determine the structures of immune regulatory sialoglycans. Microglia from mutant mouse
models will be used to test the roles of Siglecs, Siglec ligands, and Siglec ligation on microglial function.
 Aim 2: Test the role of Siglecs and Siglec ligands in AD progression in vivo. We will create mouse genetic
models lacking Siglecs and Siglec ligands crossed with human Aβ- and tau-expressing models of AD to test the
hypothesis that the Siglec regulatory pathway contributes to AD initiation and progression. Subsequently, Siglec-
humanized mice will be used to validate human Siglecs as therapeutic targets.
 Aim 3: Develop brain-deliverable Siglec inhibitors. Novel and expandable small molecule sialomimetic libra...

## Key facts

- **NIH application ID:** 10230916
- **Project number:** 1R56AG068089-01
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Tong Li
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $785,544
- **Award type:** 1
- **Project period:** 2020-09-15 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10230916

## Citation

> US National Institutes of Health, RePORTER application 10230916, Regulation of microglia in Alzheimer's Disease by Siglecs and Siglec ligands (1R56AG068089-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10230916. Licensed CC0.

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