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Evaluation of LC3-II Release via Extracellular Vesicles in Relation to the Accumulation of Intracellular LC3-positive Vesicles
Published on: October 18, 2024
BACE is degraded via the lysosomal pathway
Young Ho Koh1, Christine A F von Arnim, Bradley T Hyman
1Genetics and Aging Research Unit, Massachusetts General Hospital, Charlestown, 02129, USA.
The Journal of Biological Chemistry
|July 22, 2005
Summary
Beta-site APP cleaving enzyme (BACE) is degraded via the lysosome. A specific di-leucine motif in BACE is crucial for its lysosomal targeting and subsequent degradation.
Area of Science:
- Neuroscience
- Cell Biology
- Biochemistry
Background:
- Amyloid plaques, linked to Alzheimer's disease, involve amyloid-beta peptide aggregates.
- Beta-site APP cleaving enzyme (BACE) generates amyloid-beta peptide through APP processing.
- BACE is a transmembrane protein targeted to endosomes via a di-leucine motif.
Purpose of the Study:
- To investigate if BACE is degraded through the lysosomal pathway.
- To determine the role of the BACE di-leucine motif in lysosomal targeting.
Main Methods:
- Utilized lysosomal inhibitors (chloroquine, NH4Cl) to block degradation.
- Examined BACE localization using cell types including primary neurons.
- Assessed co-localization with lysosome-associated membrane protein 2 (LAMP2).
- Compared wild-type BACE with a di-leucine mutant (BACE-LL/AA).
Main Results:
- Lysosomal inhibitors caused BACE accumulation in various cell types.
- Inhibited lysosomal function led to BACE accumulation in late endosomal/lysosomal compartments (LAMP2-positive).
- The BACE-LL/AA mutant showed reduced co-localization with LAMP2-positive compartments.
Conclusions:
- BACE is transported to and degraded within the late endosomal/lysosomal pathway.
- The di-leucine motif is essential for efficient BACE sorting to lysosomes.
- This pathway is a key determinant of BACE regulation and amyloid-beta production.
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