# Identification of Siglecs as molecular signatures of Disease-Associated Microglia during AD Progression

> **NIH NIH R21** · JOHNS HOPKINS UNIVERSITY · 2021 · $450,313

## Abstract

PROJECT SUMMARY
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. Siglecs became a special focus of AD research when
genome-wide association studies (GWAS) discovered that a Siglec family member, CD33 (Siglec-3), was
associated with AD. Siglec-3 overexpression results in increased susceptibility to AD, and depletion decreases
susceptibility, supporting the view that Siglec-mediated inhibition restricts microglial phagocytosis and
exacerbates AD proteinopathy. As multiple inhibitory Siglecs are expressed on human (and mouse) microglia,
understanding the regulation by Siglec pathways will give us opportunity to modulate the microglia function and
prevent or slowdown the progression of AD. Transcriptome analyses has been widely used to revealed changes
in gene expression of microglia in disease. However, since different subsets of microglia display a wide range of
responses and functions, whole transcriptome analyses alone could not fully capture the context-dependent
microglia variety during disease. Recent studies with single-cell analysis have provided a high-resolution view of
the transcriptional landscape of microglia subtypes of the murine CNS during development and disease. Our
preliminary scRNA-seq and immunocytochemical analysis demonstrated that Siglecs, especially Siglec-F, and
SiglecG are associated with a specific subset of microglia that are activated at different stage of AD, which
support our hypothesis that Siglec genes are specifically expressed in subsets of microglia at particular stages
of AD. Here, we propose to use a combination of scRNA-seq and whole transcriptome sequencing analysis to
understand the relationship between Siglecs signaling and the microglial phenotypes in AD models to elucidate
the impact of microglia subtypes on AD progression. We have developed a mouse model (Tau4RΔK-AP mice)
that could mimic different stages of AD development from pre-symptomatic early stage to advance stage of AD
with widespread neuronal loss and brain atrophy, which is instrumental for the current proposal. In two aims, we
will take advantage of Tau4RΔK-AP mice and mice expressing either only Aβ plaques (APP;PS1 mice) or only
tau tangles (Tau4RΔK mice) to test the hypothesis that Siglecs regulate microglial function during AD
progression in two Aims. Aim 1: To determine whether Siglecs are specifically expressed in the subset of
microglia that are activated by AD pathologies at different stages of the disease. Aim 2: To determine the
regulation of Siglecs as signature genes in DAMs. Succe...

## Key facts

- **NIH application ID:** 10286903
- **Project number:** 1R21AG073710-01
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Tong Li
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $450,313
- **Award type:** 1
- **Project period:** 2021-09-30 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10286903

## Citation

> US National Institutes of Health, RePORTER application 10286903, Identification of Siglecs as molecular signatures of Disease-Associated Microglia during AD Progression (1R21AG073710-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10286903. Licensed CC0.

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