Camelid heavy chain only antibody fragment domain against β-site of amyloid precursor protein cleaving enzyme 1 inhibits β-secretase activity in vitro and in vivo
© 2015 FEBS..
UNLABELLED: Accumulation and aggregation of the amyloid-β (Aβ) peptide is associated with Alzheimer's disease (AD). Aβ is generated from the amyloid precursor protein by the successive action of two membrane-associated processing enzymes: β-secretase or β-site of amyloid precursor protein cleaving enzyme 1 (BACE1) and γ-secretase. Inhibition of one or both of these enzymes prevents Aβ generation and the accompanying Aβ accumulation. Antigen binding fragments from camelid heavy chain only antibodies (VHHs) were found to exert excellent enzyme inhibition activity. In the present study, we generated VHHs against BACE1 by active immunization of Lama glama with the recombinant BACE1 protein. Two classes of VHHs were selected from a VHH-phage display library by competitive elution with a peptide encoding the Swedish mutation variant of the BACE1 processing site. One VHH was found to inhibit the enzyme activity of BACE1 in vitro and in cell culture, whereas two other VHHs were found to stimulate BACE1 activity under the same conditions in vitro. Furthermore, an in vivo study with a transgenic AD mouse model, using intracisternal injection of the inhibitory VHH, led to acute reduction of the Aβ load in the blood and brain. This inhibitory VHH may be considered as a candidate molecule for a therapy directed towards reduction of Aβ load and prevention of AD progression. Both the inhibitory and stimulatory VHH may be useful for improving our understanding of the structure-function relationship of BACE1, as well as its role in AD progression.
DATABASE: The GenBank sequence accession numbers are KR363186 for VHH B1a; KR363187 for VHH B3a; and KR363188 for VHH B5a.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2015 |
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| Erschienen: |
2015 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:282 |
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| Enthalten in: |
The FEBS journal - 282(2015), 18 vom: 29. Sept., Seite 3618-31 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Dorresteijn, Bram [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 12.04.2016 Date Revised 16.09.2015 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1111/febs.13367 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM250621967 |
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| 100 | 1 | |a Dorresteijn, Bram |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Camelid heavy chain only antibody fragment domain against β-site of amyloid precursor protein cleaving enzyme 1 inhibits β-secretase activity in vitro and in vivo |
| 264 | 1 | |c 2015 | |
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| 500 | |a Date Completed 12.04.2016 | ||
| 500 | |a Date Revised 16.09.2015 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2015 FEBS. | ||
| 520 | |a UNLABELLED: Accumulation and aggregation of the amyloid-β (Aβ) peptide is associated with Alzheimer's disease (AD). Aβ is generated from the amyloid precursor protein by the successive action of two membrane-associated processing enzymes: β-secretase or β-site of amyloid precursor protein cleaving enzyme 1 (BACE1) and γ-secretase. Inhibition of one or both of these enzymes prevents Aβ generation and the accompanying Aβ accumulation. Antigen binding fragments from camelid heavy chain only antibodies (VHHs) were found to exert excellent enzyme inhibition activity. In the present study, we generated VHHs against BACE1 by active immunization of Lama glama with the recombinant BACE1 protein. Two classes of VHHs were selected from a VHH-phage display library by competitive elution with a peptide encoding the Swedish mutation variant of the BACE1 processing site. One VHH was found to inhibit the enzyme activity of BACE1 in vitro and in cell culture, whereas two other VHHs were found to stimulate BACE1 activity under the same conditions in vitro. Furthermore, an in vivo study with a transgenic AD mouse model, using intracisternal injection of the inhibitory VHH, led to acute reduction of the Aβ load in the blood and brain. This inhibitory VHH may be considered as a candidate molecule for a therapy directed towards reduction of Aβ load and prevention of AD progression. Both the inhibitory and stimulatory VHH may be useful for improving our understanding of the structure-function relationship of BACE1, as well as its role in AD progression | ||
| 520 | |a DATABASE: The GenBank sequence accession numbers are KR363186 for VHH B1a; KR363187 for VHH B3a; and KR363188 for VHH B5a | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Alzheimer's disease | |
| 650 | 4 | |a BACE1 | |
| 650 | 4 | |a VHH | |
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| 650 | 7 | |a Amyloid Precursor Protein Secretases |2 NLM | |
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| 650 | 7 | |a Aspartic Acid Endopeptidases |2 NLM | |
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| 650 | 7 | |a BACE1 protein, human |2 NLM | |
| 650 | 7 | |a EC 3.4.23.46 |2 NLM | |
| 700 | 1 | |a Rotman, Maarten |e verfasserin |4 aut | |
| 700 | 1 | |a Faber, Dorien |e verfasserin |4 aut | |
| 700 | 1 | |a Schravesande, Ruud |e verfasserin |4 aut | |
| 700 | 1 | |a Suidgeest, Ernst |e verfasserin |4 aut | |
| 700 | 1 | |a van der Weerd, Louise |e verfasserin |4 aut | |
| 700 | 1 | |a van der Maarel, Silvère M |e verfasserin |4 aut | |
| 700 | 1 | |a Verrips, Cornelis T |e verfasserin |4 aut | |
| 700 | 1 | |a El Khattabi, Mohamed |e verfasserin |4 aut | |
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