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Proximity ligation assay reveals both pre- and postsynaptic localization of the APP-processing enzymes ADAM10 and BACE1 in rat and human adult brain

Authors
  • Lundgren, Jolanta L.1
  • Vandermeulen, Lina2
  • Sandebring-Matton, Anna1
  • Ahmed, Saheeb3
  • Winblad, Bengt1
  • Di Luca, Monica2
  • Tjernberg, Lars O.1
  • Marcello, Elena2
  • Frykman, Susanne1
  • 1 Karolinska Institutet, BioClinicum J9:20, Visionsgatan 4, Solna, 171 64, Sweden , Solna (Sweden)
  • 2 Universitá Degli Studi Di Milano, Milan, Italy , Milan (Italy)
  • 3 University Medical Center, Göttingen, Germany , Göttingen (Germany)
Type
Published Article
Journal
BMC Neuroscience
Publisher
Springer (Biomed Central Ltd.)
Publication Date
Feb 04, 2020
Volume
21
Issue
1
Identifiers
DOI: 10.1186/s12868-020-0554-0
Source
Springer Nature
Keywords
License
Green

Abstract

BackgroundSynaptic degeneration and accumulation of amyloid β-peptides (Aβ) are hallmarks of the Alzheimer diseased brain. Aβ is synaptotoxic and produced by sequential cleavage of the amyloid precursor protein (APP) by the β-secretase BACE1 and by γ-secretase. If APP is instead cleaved by the α-secretase ADAM10, Aβ will not be generated. Although BACE1 is considered to be a presynaptic protein and ADAM10 has been reported to mainly localize to the postsynaptic density, we have previously shown that both ADAM10 and BACE1 are highly enriched in synaptic vesicles of rat brain and mouse primary hippocampal neurons.ResultsHere, using brightfield proximity ligation assay, we expanded our previous result in primary neurons and investigated the in situ synaptic localization of ADAM10 and BACE1 in rat and human adult brain using both pre- and postsynaptic markers. We found that ADAM10 and BACE1 were in close proximity with both the presynaptic marker synaptophysin and the postsynaptic marker PSD-95. The substrate APP was also detected both pre- and postsynaptically. Subcellular fractionation confirmed that ADAM10 and BACE1 are enriched to a similar degree in synaptic vesicles and as well as in the postsynaptic density.ConclusionsWe show that the α-secretase ADAM10 and the β-secretase BACE1 are located in both the pre- and postsynaptic compartments in intact brain sections. These findings increase our understanding of the regulation of APP processing, thereby facilitating development of more specific treatment strategies.

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