# Structural basis of CD33 receptor signaling in Alzheimer's disease

> **NIH NIH R03** · UNIVERSITY OF SOUTHERN CALIFORNIA · 2020 · $165,000

## Abstract

Project Summary
Alzheimer's disease (AD) is a fatal neurodegenerative disorder that affects 10-30% of the population over 65
years old. The pathology of the disease is characterized by the failure to clear extracellular amyloid-β (Aβ) pep-
tides and intracellular neurofibrillary tangles from the brain. In the continued absence of an AD therapy, the
disease is persistent, disabling, costly and ultimately fatal. Microglia, the resident phagocytes of the central
nervous system, play a major role in the clearance of Aβ aggregates. The activation state and phagocytosis
capability of microglia are modulated by the CD33 cell-surface receptor. Specifically, the AD risk allele
rs3865444 is associated with higher levels of CD33 that suppress microglial phagocytosis. In contrast, CD33
inactivation improves phagocytosis and mitigates Aβ pathology. CD33 inhibition may thus represent a novel
therapy for AD and, to aid in this endeavor, the current proposals aims to understand the structural basis of
CD33 signaling. To ascertain the mechanism of signal transduction across the cell membrane, in Aim 1 the TM
domain border, the aggregation state of the TM domain, and the structure and dynamics of the TM and cyto-
solic domains will be determined by solution NMR spectroscopy. To connect ligand binding and associated bio-
logical effects with structural events that provide first insight into the mechanism of TM signaling, in Aim 2 the
CD33-binding sites and affinities of two cytosolic ligands will be characterized by NMR and ITC. The binding
sites further identify the structural and functional roles of the cytosolic receptor tail and provide insight into as-
sembly of cytosolic signaling complexes. CD33 belongs to the family of sialic acid-binding immunoglobulin-like
receptors (Siglecs) that regulate the function of cells in the innate and adaptive immune systems through the
recognition of their glycan ligands. The proposed research provide basic insight into the little understood struc-
tural basis of Siglec signaling, identifies targets sites and sequences for the pharmaceutical intervention in
CD33 signaling and, thus, offers a direct avenue to therapeutic AD intervention.

## Key facts

- **NIH application ID:** 9901449
- **Project number:** 5R03AG063284-02
- **Recipient organization:** UNIVERSITY OF SOUTHERN CALIFORNIA
- **Principal Investigator:** Tobias Sebastian Ulmer
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $165,000
- **Award type:** 5
- **Project period:** 2019-04-01 → 2022-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9901449

## Citation

> US National Institutes of Health, RePORTER application 9901449, Structural basis of CD33 receptor signaling in Alzheimer's disease (5R03AG063284-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9901449. Licensed CC0.

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