期刊
ACTA NEUROPATHOLOGICA
卷 144, 期 5, 页码 911-938出版社
SPRINGER
DOI: 10.1007/s00401-022-02499-0
关键词
Alzheimer's disease; Amyloid-beta precursor protein; Mitochondria; CHCHD6; Neuroprotection; Neurodegeneration
资金
- US National Institutes of Health (NIH) [R01AG065240, R01NS115903, R01AG076051, RF1AG074346]
- NIH [R01 AG057557, AG061388, AG062272, AG076649]
- Dr. Ralph and Marian Falk Medical Research Trust-Transformative Award
- Case Western Reserve University
- AHA/Allen Initiative in Brain Health and Cognitive Impairment [19PABH134580006]
- Elizabeth Ring Mather & William Gwinn Mather Fund
- S. Livingston Samuel Mather Trust
- G.R. Lincoln Family Foundation
- Wick Foundation
- Leonard Krieger Fund of the Cleveland Foundation
- Gordon Evie Safran
- Louis Stokes VA Medical Center resources and facilities
This study reveals that CHCHD6 mechanistically connects APP processing and mitochondrial dysfunction in Alzheimer's disease through a circular feedback loop. Reduced CHCHD6 enhances APP accumulation on mitochondria-associated ER membranes, accelerates APP processing, and induces mitochondrial dysfunction and neuronal cholesterol accumulation, promoting amyloid pathology in Alzheimer's disease.
The mechanistic relationship between amyloid-beta precursor protein (APP) processing and mitochondrial dysfunction in Alzheimer's disease (AD) has long eluded the field. Here, we report that coiled-coil-helix-coiled-coil-helix domain containing 6 (CHCHD6), a core protein of the mammalian mitochondrial contact site and cristae organizing system, mechanistically connects these AD features through a circular feedback loop that lowers CHCHD6 and raises APP processing. In cellular and animal AD models and human AD brains, the APP intracellular domain fragment inhibits CHCHD6 transcription by binding its promoter. CHCHD6 and APP bind and stabilize one another. Reduced CHCHD6 enhances APP accumulation on mitochondria-associated ER membranes and accelerates APP processing, and induces mitochondrial dysfunction and neuronal cholesterol accumulation, promoting amyloid pathology. Compensation for CHCHD6 loss in an AD mouse model reduces AD-associated neuropathology and cognitive impairment. Thus, CHCHD6 connects APP processing and mitochondrial dysfunction in AD. This provides a potential new therapeutic target for patients.
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