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Alzheimer'S & Dementia : the Journal of the Alzheimer'S Association
|December 25, 2025
PubMed
Summary
This summary is machine-generated.

This study shows that the anti-SIGLEC10 antibody ONC-841 clears amyloid plaques and reduces tau biomarkers in Alzheimer's disease (AD) mouse models. ONC-841 rejuvenates microglial functions, offering a potential new immunotherapy for AD.

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Area of Science:

  • Neuroscience
  • Immunology
  • Pharmacology

Background:

  • Microglial dysfunction is implicated in Alzheimer's disease (AD) pathogenesis.
  • Existing microglial-targeting therapies have not yielded clinical benefits for AD patients.
  • SIGLEC10, exclusively expressed in brain microglia, plays a role in AD.

Purpose of the Study:

  • To investigate the therapeutic potential of ONC-841, an anti-SIGLEC10 monoclonal antibody, in AD mouse models.
  • To evaluate ONC-841's ability to cross the blood-brain barrier and target microglial SIGLEC10.
  • To assess ONC-841's efficacy in reducing AD pathology and its mechanism of action.

Main Methods:

  • Developed SIGLEC10-expressing AD mouse models by crossing AD models with human SIGLEC transgenic mice.
  • Administered ONC-841 intravenously and confirmed blood-brain barrier penetration and microglial SIGLEC10 occupancy.
  • Assessed amyloid plaque and pTau accumulation, measured plasma biomarkers, and investigated the mechanism of action via single nuclear RNA sequencing and in vitro phagocytosis assays.

Main Results:

  • ONC-841 treatment led to significant clearance of amyloid-beta plaques in the brain.
  • Reduced plasma levels of pTau181 and total Tau were observed in treated mice.
  • ONC-841 enhanced microglial phagocytosis of protein aggregates and rejuvenated microglial functions.

Conclusions:

  • The anti-SIGLEC10 antibody ONC-841 demonstrates therapeutic activity in AD mouse models.
  • ONC-841 promotes the clearance of amyloid plaques and reduces tau biomarkers by rejuvenating microglial functions.
  • These findings support the clinical development of ONC-841 as a microglia-targeting immunotherapy for Alzheimer's disease.