Lymphoid gene expression supports neuroprotective microglia function
NatureTL;DR
Brain immune cells called microglia can either protect against or worsen Alzheimer's disease, and scientists found that a specific protein called CD28 helps these cells stay in "protective mode" by reducing harmful brain inflammation. This discovery could lead to new treatments that boost the brain's natural defenses against Alzheimer's.
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 neurotoxic 2 . 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 activation 3,4 . Microglia-specific deficiency in CD28, which is expressed by a small subset of plaque-associated PU.1 low microglia, promotes a broad inflammatory microglial state that is associated with increased amyloid plaque load. Our findings indicate that PU.1 low 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.
- 1Microglia brain immune cells have both protective and harmful responses to amyloid plaques in Alzheimer's disease
- 2The transcription factor PU.1 controls protective microglial function but gets turned down when microglia encounter amyloid plaques
- 3CD28, a receptor protein normally found on immune T cells, is expressed by a small subset of protective microglia near plaques
- 4Mice lacking CD28 in their microglia showed increased brain inflammation and more amyloid plaque buildup
- 5PU.1-low, CD28-expressing microglia act as suppressive cells that reduce neuroinflammation and slow Alzheimer's progression
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