| RRC ID |
87301
|
| Author |
Shang Y, Sun X, Chen X, Wang Q, Wang EJ, Miller E, Xu R, Pieper AA, Qi X.
|
| Title |
A CHCHD6-APP axis connects amyloid and mitochondrial pathology in Alzheimer's disease.
|
| Journal |
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.
|
| Volume |
144(5)
|
| Pages |
911-938
|
| Published |
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
|
| Resource |
| Mice |
RBRC06343
RBRC06344 |
