# Dissecting the role of NEU1-dependent de-sialylation in neurodegeneration and neuroinflammation

> **NIH NIH RF1** · ST. JUDE CHILDREN'S RESEARCH HOSPITAL · 2021 · $1,750,578

## Abstract

ABSTRACT
Changes in the sialic acid content of neural glycoproteins have been reported in neurodegenerative and
neuroinflammatory diseases, including Alzheimer’s disease (AD). However, how these changes govern
neuropathogenic processes remains poorly understood. The central hypothesis of these studies is that
impaired de-sialylation affects the physiological and functional properties of specific sialo-glycoproteins in
neurons and microglia, initiating a pathogenic cascade leading to neurodegeneration and neuroinflammation.
We will test this hypothesis from the angle of the sialic acid-cleaving enzyme NEU1, a lysosomal sialidase,
using a mouse model of the lysosomal storage disease, sialidosis, as an experimental tool. We have shown
that Neu1–/– mice develop a hippocampal neuropathology with features of an amyloidosis, including
accumulation of an oversialylated APP, a substrate of NEU1, and widespread neuroinflammation. Ablating
NEU1 expression in a canonical model of AD (5xFAD) leads to exacerbation of the amyloidosis phenotype,
while increasing NEU1 expression, via a gene therapy approach, reduces plaque formation. These findings
implicate NEU1 as the potential underpinning cause, although the mechanisms linking the cause to the effects
still need to be deciphered. The studies proposed in this application are directed to closing this knowledge
gap, because of these previous observations and new compelling preliminary data. Besides APP, we have
identified additional potential substrates of NEU1, including those that participate directly in the amyloidogenic
process (BACE1 and nicastrin) and those that are responsible for neuroinflammatory processes, such as
microglial phagocytosis (CD68 and TREM2). We will explore the idea that by controlling the levels of sialic
acids on these specific AD-related glycoproteins in neurons (Aim 1) and microglia (Aim 2), NEU1 functions as
a crucial regulator of key biological processes that maintain brain homeostasis. In Aim 1, we will examine the
effects of altered sialylation on APP, and its sialylated proteolytic enzymes, BACE1 and nicastrin, in Neu1–/–
mice and in established AD mouse models crossed into the Neu1–/– background. We will use a combination
of subcellular fractionation methods, immunofluorescent microscopy, and high-resolution 3D imaging to
determine alterations in intracellular distribution, processing and turnover rate of these glycoproteins. In Aim2,
we will study how impaired de-sialylation of microglial receptors and signaling proteins affects their subcellular
localization, turnover rate, and the cellular functions they are known to control. To focus our studies exclusively
on microglia we will cross the above-mentioned mice with a mouse model that expresses GFP almost solely
in microglia. Overall the experimental design of this grant application will enable us to elucidate mechanisms
of pathogenesis leading to neuronal and microglial dysfunction with direct translational implications for
pa...

## Key facts

- **NIH application ID:** 10279649
- **Project number:** 1RF1NS123174-01
- **Recipient organization:** ST. JUDE CHILDREN'S RESEARCH HOSPITAL
- **Principal Investigator:** ALESSANDRA D'AZZO
- **Activity code:** RF1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $1,750,578
- **Award type:** 1
- **Project period:** 2021-07-15 → 2024-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10279649

## Citation

> US National Institutes of Health, RePORTER application 10279649, Dissecting the role of NEU1-dependent de-sialylation in neurodegeneration and neuroinflammation (1RF1NS123174-01). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10279649. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*