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Isolation of Cortical Microglia with Preserved Immunophenotype and Functionality From Murine Neonates
Published on: January 30, 2014
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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
Summary
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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