• Bram Dorresteijn, Maarten Rotman, Dorien Faber, Ruud Schravesande, Ernst Suidgeest, Louise van der Weerd, Silvère M van der Maarel, Cornelis T Verrips, and Mohamed El Khattabi.
• Biomolecular Imaging Group, Division of Cell Biology, Department of Biology, Faculty of Science, Utrecht University, The Netherlands.
• FEBS J. 2015 Sep 1; 282 (18): 3618-31.

UnlabelledAccumulation 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.DatabaseThe GenBank sequence accession numbers are KR363186 for VHH B1a; KR363187 for VHH B3a; and KR363188 for VHH B5a.© 2015 FEBS.

37 keywords...

hide…