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ADAM10 and BACE1 are localized to synaptic vesicles.

Lundgren, Jolanta L; Ahmed, Saheeb; Schedin-Weiss, Sophia; Gouras, Gunnar LU ; Winblad, Bengt; Tjernberg, Lars O and Frykman, Susanne (2015) In Journal of Neurochemistry 135(3). p.606-615
Abstract
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... (More)
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. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Journal of Neurochemistry
volume
135
issue
3
pages
606 - 615
publisher
Wiley-Blackwell
external identifiers
  • pmid:26296617
  • wos:000363261700015
  • scopus:84945475896
ISSN
1471-4159
DOI
10.1111/jnc.13287
language
English
LU publication?
yes
id
9ff5eb78-f507-4513-97a6-60f65f7ce73e (old id 7840316)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/26296617?dopt=Abstract
date added to LUP
2015-09-06 16:37:23
date last changed
2017-10-01 03:03:57
@article{9ff5eb78-f507-4513-97a6-60f65f7ce73e,
  abstract     = {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.},
  author       = {Lundgren, Jolanta L and Ahmed, Saheeb and Schedin-Weiss, Sophia and Gouras, Gunnar and Winblad, Bengt and Tjernberg, Lars O and Frykman, Susanne},
  issn         = {1471-4159},
  language     = {eng},
  number       = {3},
  pages        = {606--615},
  publisher    = {Wiley-Blackwell},
  series       = {Journal of Neurochemistry},
  title        = {ADAM10 and BACE1 are localized to synaptic vesicles.},
  url          = {http://dx.doi.org/10.1111/jnc.13287},
  volume       = {135},
  year         = {2015},
}