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ADAM10 and BACE1 are localized to synaptic vesicles.

På svenska

Author

  • Jolanta L Lundgren
  • Saheeb Ahmed
  • Sophia Schedin-Weiss
  • Gunnar Gouras
  • Bengt Winblad
  • Lars O Tjernberg
  • Susanne Frykman

Summary, in English

Synaptic degeneration and accumulation of the neurotoxic amyloid β-peptide (Aβ) in the brain are hallmarks of Alzheimer disease. Aβ is produced by sequential cleavage of its precursor protein, APP, by the β-secretase BACE1 and γ-secretase. However, Aβ generation is precluded if APP is cleaved by the α-secretase ADAM10 instead of BACE1. We have previously shown that Aβ can be produced locally at the synapse. To study the synaptic localization of the APP processing enzymes we used western blotting to demonstrate that, compared to total brain homogenate, ADAM10 and BACE1 were greatly enriched in synaptic vesicles isolated from rat brain using controlled-pore glass chromatography, whereas Presenilin1 was the only enriched component of the γ-secretase complex. Moreover, we detected ADAM10 activity in synaptic vesicles and enrichment of the intermediate APP-C-terminal fractions (APP-CTFs). We confirmed the western blotting findings using in situ proximity ligation assay to demonstrate close proximity of ADAM10 and BACE1 with the synaptic vesicle marker synaptophysin in intact mouse primary hippocampal neurons. In contrast, only sparse co-localization of active γ-secretase and synaptophysin was detected. These results indicate that the first step of APP processing occurs in synaptic vesicles whereas the final step is more likely to take place elsewhere. This article is protected by copyright. All rights reserved.

Publishing year

2015

Language

English

Pages

606-615

Publication/Series

Journal of Neurochemistry

Volume

135

Issue

3

Document type

Journal article

Publisher

Wiley-Blackwell

Topic

  • Neurosciences

Status

Published

Research group

  • Experimental Dementia Research

ISBN/ISSN/Other

  • ISSN: 1471-4159