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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
Author(s) -
Dorresteijn Bram,
Rotman Maarten,
Faber Dorien,
Schravesande Ruud,
Suidgeest Ernst,
Weerd Louise,
Maarel Silvère M.,
Verrips Cornelis T.,
El Khattabi Mohamed
Publication year - 2015
Publication title -
the febs journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 204
eISSN - 1742-4658
pISSN - 1742-464X
DOI - 10.1111/febs.13367
Subject(s) - amyloid precursor protein , in vivo , in vitro , enzyme , microbiology and biotechnology , epitope , single domain antibody , biochemistry , recombinant dna , p3 peptide , chemistry , antibody , phage display , amyloid precursor protein secretase , peptide , biology , alzheimer's disease , gene , immunology , medicine , disease , pathology
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 ( BACE 1) 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 ( VHH s) were found to exert excellent enzyme inhibition activity. In the present study, we generated VHH s against BACE 1 by active immunization of Lama glama with the recombinant BACE 1 protein. Two classes of VHH s were selected from a VHH ‐phage display library by competitive elution with a peptide encoding the Swedish mutation variant of the BACE 1 processing site. One VHH was found to inhibit the enzyme activity of BACE 1 in vitro and in cell culture, whereas two other VHH s were found to stimulate BACE 1 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 BACE 1, 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.