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Updated: May 5, 2026
Isolation of Cortical Microglia with Preserved Immunophenotype and Functionality From Murine Neonates
Published on: January 30, 2014
Epigenetic control of microglial mitochondrial immunity by KAT7 drives Alzheimer's disease pathogenesis
Yongqing Liu1, Minghua Fan2, Yingzhi Ye1
1Department of Physiology, Pharmacology and Therapeutics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Abstract:
Mitochondrial DNA (mtDNA)-driven innate immune signaling sustains chronic neuroinflammation in neurological diseases such as Alzheimer's disease (AD), yet how this pathway is regulated in microglia remains poorly understood. Here, we identify the histone acetyltransferase KAT7 (HBO1) as a central epigenetic regulator that links chromatin remodeling to mitochondrial immune activation. KAT7 and its histone mark H3K14ac are elevated in microglia from 5×FAD mice and human AD brains. Integrative transcriptomic and epigenomic analyses reveal that KAT7 activates transcription of Cmpk2, a mitochondrial kinase essential for mtDNA synthesis. Loss of KAT7 reduces Cmpk2 expression, impairs mtDNA replication and release, and consequently suppresses cGAS-STING and NLRP3 signaling. Importantly, both microglia-specific deletion and pharmacological inhibition of KAT7 mitigate cytosolic mtDNA-induced neuroinflammation, decrease amyloid-β burden, restore synaptic plasticity, and improve cognitive function in 5×FAD mice. Together, these findings uncover an epigenetic-mitochondrial axis sustaining microglial pathogenicity and establish KAT7 as a promising therapeutic target for AD.
Insights
Researchers found that KAT7 regulates mitochondrial DNA release in microglia, a key driver of neuroinflammation in Alzheimer's disease. Inhibiting KAT7 reduced inflammation and improved cognitive function in mouse models.
Area of Science:
- Neuroscience
- Immunology
- Epigenetics
Background:
- Mitochondrial DNA (mtDNA) signaling drives neuroinflammation in Alzheimer's disease (AD).
- Regulation of this pathway in microglia, the brain's immune cells, is not well understood.
- Microglia play a critical role in AD pathogenesis.
Purpose of the Study:
- To identify epigenetic regulators of mitochondrial immune activation in microglia.
- To investigate the role of KAT7 in AD-related neuroinflammation.
- To explore KAT7 as a potential therapeutic target for AD.
Main Methods:
- Integrative transcriptomic and epigenomic analyses in 5×FAD mice and human AD brains.
- Microglia-specific KAT7 deletion and pharmacological inhibition.
- Assessment of mtDNA replication, release, and innate immune signaling (cGAS-STING, NLRP3).
- Evaluation of amyloid-β burden, synaptic plasticity, and cognitive function.
Main Results:
- KAT7 and H3K14ac are elevated in AD microglia.
- KAT7 activates transcription of Cmpk2, essential for mtDNA synthesis.
- Loss of KAT7 reduces mtDNA replication/release and suppresses cGAS-STING/NLRP3 signaling.
- KAT7 inhibition mitigated neuroinflammation, amyloid-β, and cognitive deficits in 5×FAD mice.
Conclusions:
- KAT7 acts as a crucial epigenetic regulator linking chromatin remodeling to microglial mitochondrial immune activation.
- An epigenetic-mitochondrial axis drives microglial pathogenicity in AD.
- Targeting KAT7 offers a promising therapeutic strategy for Alzheimer's disease.
