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Published on: April 13, 2017
Lymphoid gene expression supports neuroprotective microglia function
Pinar Ayata1,2,3, Jessica M Crowley4, Matthew F Challman4
1Nash Family Department of Neuroscience, Department of Psychiatry, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. payata@gc.cuny.edu.
Abstract:
Microglia, the innate immune cells of the brain, play a defining role in the progression of Alzheimer's disease (AD)1. The microglial response to amyloid plaques in AD can range from neuroprotective to neurotoxic2. Here we show that the protective function of microglia is governed by the transcription factor PU.1, which becomes downregulated following microglial contact with plaques. Lowering PU.1 expression in microglia reduces the severity of amyloid disease pathology in mice and is linked to the expression of immunoregulatory lymphoid receptor proteins, particularly CD28, a surface receptor that is critical for T cell activation3,4. Microglia-specific deficiency in CD28, which is expressed by a small subset of plaque-associated PU.1low microglia, promotes a broad inflammatory microglial state that is associated with increased amyloid plaque load. Our findings indicate that PU.1low CD28-expressing microglia may operate as suppressive microglia that mitigate the progression of AD by reducing the severity of neuroinflammation. This role of CD28 and potentially other lymphoid co-stimulatory and co-inhibitory receptor proteins in governing microglial responses in AD points to possible immunotherapy approaches for treating the disease by promoting protective microglial functions.
Insights
Microglia
Area of Science:
- Neuroscience
- Immunology
- Genetics
Background:
- Microglia, the brain's immune cells, are crucial in Alzheimer's disease (AD) progression.
- Their response to amyloid plaques can be either protective or harmful.
- The transcription factor PU.1 influences microglial function in AD.
Purpose of the Study:
- To investigate the role of transcription factor PU.1 in microglial function during Alzheimer's disease.
- To explore the connection between PU.1, CD28 expression, and microglial responses to amyloid plaques.
- To identify potential immunotherapy targets for AD based on microglial function.
Main Methods:
- Studied the regulation of PU.1 in microglia upon contact with amyloid plaques.
- Investigated the impact of reduced PU.1 expression on AD pathology in mouse models.
- Analyzed the role of CD28, a lymphoid receptor, in microglia-associated inflammation and AD progression.
Main Results:
- Downregulation of PU.1 in microglia near amyloid plaques was observed.
- Reduced PU.1 expression ameliorated amyloid disease pathology in mice.
- Microglia-specific CD28 deficiency promoted a pro-inflammatory state and increased amyloid plaque load.
- PU.1low CD28-expressing microglia exhibited suppressive functions, mitigating neuroinflammation.
Conclusions:
- PU.1 is a key regulator of protective microglial functions in Alzheimer's disease.
- CD28-expressing microglia may act as suppressors of neuroinflammation, slowing AD progression.
- Targeting microglial PU.1 and CD28 pathways offers potential for novel AD immunotherapies.
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