Back to Search
Start Over
Clathrin adaptor AP-1–mediated Golgi export of amyloid precursor protein is crucial for the production of neurotoxic amyloid fragments
- Source :
- Journal of Biological Chemistry. 298:102172
- Publication Year :
- 2022
- Publisher :
- Elsevier BV, 2022.
-
Abstract
- One of the hallmarks of Alzheimer's disease is the accumulation of toxic amyloid-β (Aβ) peptides in extracellular plaques. The direct precursor of Aβ is the carboxyl-terminal fragment β (or C99) of the amyloid precursor protein (APP). C99 is detected at elevated levels in Alzheimer's disease brains, and its intracellular accumulation has been linked to early neurotoxicity independently of Aβ. Despite this, the causes of increased C99 levels are poorly understood. Here, we demonstrate that APP interacts with the clathrin vesicle adaptor AP-1 (adaptor protein 1), and we map the interaction sites on both proteins. Using quantitative kinetic trafficking assays, established cell lines and primary neurons, we also show that this interaction is required for the transport of APP from the trans-Golgi network to endosomes. In addition, disrupting AP-1-mediated transport of APP alters APP processing and degradation, ultimately leading to increased C99 production and Aβ release. Our results indicate that AP-1 regulates the subcellular distribution of APP, altering its processing into neurotoxic fragments.
- Subjects :
- Amyloid beta-Peptides
Golgi Apparatus
adaptor protein 1
amyloid precursor protein
Amyloidosis
Cell Biology
protein trafficking (Golgi)
Biochemistry
Transcription Factor AP-1
Adaptor Proteins, Vesicular Transport
Amyloid beta-Protein Precursor
Alzheimer Disease
mental disorders
Humans
Neurotoxicity Syndromes
Amyloid Precursor Protein Secretases
Alzheimer’s disease
endosome
Molecular Biology
Subjects
Details
- ISSN :
- 00219258
- Volume :
- 298
- Database :
- OpenAIRE
- Journal :
- Journal of Biological Chemistry
- Accession number :
- edsair.doi.dedup.....087570cd2b9e46b2dbe56eb76aa9ee57