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Updated: Jun 11, 2026
Mitochondrial Preparation from Microglia for Glycan Analysis
Published on: May 30, 2025
Epigenetic control of microglial mitochondrial immunity by KAT7 drives Alzheimer's disease pathogenesis
Yongqing Liu1, Yingzhi Ye1, Minghua Fan2
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 cytidine/uridine monophosphate kinase 2 (Cmpk2), a mitochondrial kinase essential for mtDNA synthesis. Loss of KAT7 reduces Cmpk2 expression, impairs mtDNA replication and release, and consequently suppresses cyclic guanosine monophosphate-AMP synthase (cGAS)-stimulator of interferon genes (STING) and NLRP3 signaling. Importantly, both microglia-specific deletion and pharmacological inhibition of KAT7 mitigate cytosolic mtDNA-induced neuroinflammation, decrease β-amyloid 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 potential therapeutic target for AD.
Insights
The histone acetyltransferase KAT7 regulates mitochondrial DNA immune signaling in microglia, a key factor in Alzheimer's disease (AD) neuroinflammation. Inhibiting KAT7 reduces AD pathology and improves cognitive function, suggesting it as a therapeutic target.
Area of Science:
- Neuroscience
- Immunology
- Epigenetics
Background:
- Mitochondrial DNA (mtDNA)-driven innate immune signaling contributes to chronic neuroinflammation in Alzheimer's disease (AD).
- The precise regulation of this pathway in microglia, the brain's resident immune cells, is not well understood.
Purpose of the Study:
- To identify epigenetic regulators of mitochondrial immune activation in microglia.
- To investigate the role of histone acetyltransferase KAT7 (HBO1) in AD pathogenesis.
Main Methods:
- Integrative transcriptomic and epigenomic analyses in 5×FAD mouse models and human AD brains.
- Assessment of KAT7's effect on Cmpk2 expression, mtDNA replication, and innate immune signaling pathways (cGAS-STING, NLRP3).
- Evaluation of microglia-specific KAT7 deletion and pharmacological inhibition in 5×FAD mice.
Main Results:
- KAT7 and H3K14ac are elevated in microglia from AD models and patients.
- KAT7 epigenetically activates Cmpk2, a kinase crucial for mtDNA synthesis.
- Loss of KAT7 suppresses mtDNA release and downstream cGAS-STING/NLRP3 signaling.
- KAT7 inhibition mitigates neuroinflammation, reduces amyloid burden, and improves cognitive deficits in AD mice.
Conclusions:
- KAT7 acts as a critical epigenetic regulator linking chromatin remodeling to mitochondrial immune activation in microglia.
- The identified epigenetic-mitochondrial axis drives microglial pathogenicity in AD.
- KAT7 represents a promising therapeutic target for Alzheimer's disease.
