論文 - 詳細
| RRC ID | 87301 |
|---|---|
| 著者 | Shang Y, Sun X, Chen X, Wang Q, Wang EJ, Miller E, Xu R, Pieper AA, Qi X. |
| タイトル | A CHCHD6-APP axis connects amyloid and mitochondrial pathology in Alzheimer's disease. |
| ジャーナル | Acta Neuropathol |
| Abstract |
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. |
| 巻・号 | 144(5) |
| ページ | 911-938 |
| 公開日 | 2022-11-1 |
| DOI | 10.1007/s00401-022-02499-0 |
| PII | 10.1007/s00401-022-02499-0 |
| PMID | 36104602 |
| PMC | PMC9547808 |
| MeSH | Alzheimer Disease* / pathology Amyloid / metabolism Amyloid beta-Peptides / metabolism Amyloid beta-Protein Precursor / genetics Amyloid beta-Protein Precursor / metabolism Amyloidosis* / metabolism Animals Disease Models, Animal Humans Mammals / metabolism Mice Mice, Transgenic Mitochondria / metabolism Mitochondrial Membranes / metabolism Mitochondrial Proteins |
| IF | 14.256 |
| オルトメトリクス指標 |
オルトメトリクス指標項目
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| 最多言及媒体 | X(Twitter) |
| 各媒体での言及数の合計 | 6 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.0 |
| リソース情報 | |
| 実験動物マウス | RBRC06343 RBRC06344 |