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Updated: Jun 23, 2026

Isolation of Cortical Microglia with Preserved Immunophenotype and Functionality From Murine Neonates
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INPP5D regulates inflammasome activation in human microglia

Vicky Chou1, Richard V Pearse1, Aimee J Aylward1

  • 1Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.

Nature Communications
|November 28, 2023
PubMed

Insights

Reduced inositol polyphosphate-5-phosphatase D (INPP5D) activity in microglia drives Alzheimer's disease (AD) neuroinflammation by activating the NLRP3 inflammasome. This highlights INPP5D as a potential therapeutic target for AD.

Area of Science:

  • Neuroscience
  • Immunology
  • Genetics

Background:

  • Microglia and neuroinflammation are key in Alzheimer's disease (AD) pathogenesis.
  • Inositol polyphosphate-5-phosphatase D (INPP5D/SHIP1), a myeloid-expressed gene, is genetically linked to AD risk.

Purpose of the Study:

  • To investigate the molecular mechanisms by which INPP5D influences microglia function in AD.
  • To explore the role of INPP5D in neuroinflammation and its association with AD.

Main Methods:

  • Unbiased RNA and protein profiling of INPP5D-disrupted iPSC-derived human microglia.
  • Pharmacological validation of INPP5D activity on inflammasome components.
  • Multi-analytic examination of human brain tissue from AD patients and controls.

Main Results:

  • Reduced INPP5D activity correlates with disrupted autophagy and inflammasome activation.
  • Pharmacological inhibition of INPP5D promotes NLRP3 inflammasome assembly, CASP1 cleavage, and IL-1β/IL-18 secretion.
  • Reduced INPP5D function in human microglia is linked to inflammasome activation in AD brains.

Conclusions:

  • Decreased INPP5D activity in microglia contributes to AD pathogenesis via inflammasome activation.
  • Targeting the inflammasome pathway offers a potential therapeutic strategy for AD, particularly for individuals with reduced INPP5D function.

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