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ADAM10 and BACE1 are localized to synaptic vesicles
Jolanta L Lundgren1, Saheeb Ahmed2, Sophia Schedin-Weiss1
1Karolinska Institutet, Department of Neurobiology, Care Science and Society, Division of Neurogeriatrics, Center for Alzheimer Research, Huddinge, Sweden.
Journal of Neurochemistry
|August 23, 2015
Summary
Alzheimer disease involves amyloid-beta (Aβ) peptide accumulation. This study shows that key enzymes for Aβ production, ADAM10 and BACE1, are located in synaptic vesicles, suggesting initial processing occurs at the synapse.
Area of Science:
- Neuroscience
- Molecular Biology
- Biochemistry
Background:
- Alzheimer disease (AD) is characterized by synaptic degeneration and amyloid-beta (Aβ) peptide accumulation in the brain.
- Aβ is generated through sequential cleavage of the amyloid precursor protein (APP) by BACE1 and γ-secretase.
- Alternative APP cleavage by α-secretase (ADAM10) prevents Aβ generation.
Purpose of the Study:
- To investigate the synaptic localization of enzymes involved in amyloid precursor protein (APP) processing.
- To determine where the initial and final steps of APP cleavage occur within neurons.
Main Methods:
- Western blotting of isolated rat brain synaptic vesicles.
- Controlled-pore glass chromatography for synaptic vesicle isolation.
- In situ proximity ligation assay in mouse primary hippocampal neurons.
- Detection of ADAM10 activity and APP-C-terminal fragments (APP-CTFs).
Main Results:
- ADAM10 and BACE1 were significantly enriched in synaptic vesicles compared to total brain homogenate.
- Presenilin1 was the only enriched γ-secretase component in synaptic vesicles.
- ADAM10 activity and APP-CTFs were detected within synaptic vesicles.
- ADAM10 and BACE1 showed close proximity to the synaptic vesicle marker synaptophysin.
- Active γ-secretase showed sparse co-localization with synaptophysin.
Conclusions:
- The initial cleavage of APP by ADAM10 and BACE1 occurs within synaptic vesicles.
- The final cleavage step by γ-secretase is unlikely to occur in synaptic vesicles.
- These findings suggest that synaptic vesicles are a key site for early APP processing in the context of Alzheimer disease.
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