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Cited by 29Neuroinflammation and Neurodegeneration MechanismsGlycosylation and Glycoproteins ResearchPhagocytosis and Immune Regulation

Neuraminidase 1 regulates neuropathogenesis by governing the cellular state of microglia via modulation of Trem2 sialylation

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Fremuth, Leigh Ellen, Hu, Huimin, van de Vlekkert, Diantha, Annunziata, Ida, Weesner, Jason Andrew, Alessandra d’Azzo·2025·Cell Reports
DOI 10.1016/j.celrep.2024.115204PMC PMC11874873
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Abstract

Neuraminidase 1 (NEU1) cleaves terminal sialic acids from sialoglycoproteins in endolysosomes and at the plasma membrane. As such, NEU1 regulates immune cells, primarily those of the monocytic lineage. Here, we examine how Neu1 influences microglia by modulating the sialylation of full-length Trem2 (Trem2-FL), a multifunctional receptor that regulates microglial survival, phagocytosis, and cytokine production. When Neu1 is deficient/downregulated, Trem2-FL remains sialylated, accumulates intracellularly, and is excessively cleaved into a C-terminal fragment (Trem2-CTF) and an extracellular soluble domain (sTrem2), enhancing their signaling capacities. Sialylated Trem2-FL (Sia-Trem2-FL) does not hinder Trem2-FL-DAP12-Syk complex assembly but impairs signal transduction through Syk, ultimately abolishing Trem2-dependent phagocytosis. Concurrently, Trem2-CTF-DAP12 complexes dampen NF-κB signaling, while sTrem2 propagates Akt-dependent cell survival and NFAT1-mediated production of TNF-α and CCL3. Because NEU1 and Trem2 are implicated in neurodegenerative/neuroinflammatory diseases, including Alzheimer disease and sialidosis, modulating NEU1 activity represents a therapeutic approach to broadly regulate microglia-mediated neuroinflammation.

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  • Lysosomal exocytosis secretes lysosomal contents, including Aβ peptides and active enzymes, into the extracellular space.

    “Additionally, we find that Neu1 dysregulation leads to a marked increase in lysosomal exocytosis, a mechanism through which lysosomal contents, including Aβ peptides and active enzymes, are secreted into the extracellular space 35,38,39 .”

    From Targeting Lysosomal Dysfunction to Alleviate Plaque Deposition in an Alzheimer Disease Model (2025) · cites this paper as [39]

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Cited by

Sorted by citations

Authors
Fremuth, L. E., Hu, H., van de Vlekkert, D., Annunziata, I., Weesner, J. A., & d’Azzo, A.
Affiliations
St. Jude Children's Research Hospital (US)
Corresponding author
Alessandra d’Azzo
ORCID
Venue
Cell Reports
Publisher
Elsevier BV
Published
2025-01
Volume
44
Issue
1
Pages
115204
ISSN
2211-1247 (ISSN-L)
DOI
10.1016/j.celrep.2024.115204
PMC
PMC11874873
OpenAlex
W4406364909
Cited by
29
References
7
Citations by year
2026: 15 · 2025: 14
FWCI
9.42
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell Reports (publishedVersion, cc-by-nc-nd)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion, cc-by-nc-nd)
  • PubMed Central (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Institutes of Health (P30CA021765)
  • National Institute of Neurological Disorders and Stroke (1RF1NS123174-01)
  • American Lebanese Syrian Associated Charities (P30CA021765)
  • Assisi Foundation of Memphis Inc
  • National Institute of General Medical Sciences (R01GM104981-04)
Topics
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Glycosylation and Glycoproteins Research
  • Life Sciences › Immunology and Microbiology › Immunology › Phagocytosis and Immune Regulation
Keywords
NEU1, TREM2, sialylation, microglia, sTREM2, phagocytosis, NF-κB signaling, Akt signaling, NFAT1, TNF-α, CCL3, neuroinflammation, neurodegenerative diseases, Alzheimer's disease, sialidosis, sialic acid

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