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A\u03b2 is generated from the amyloid precursor protein by the successive action of two membrane\u2010associated processing enzymes: \u03b2\u2010secretase or \u03b2\u2010site of amyloid precursor protein cleaving enzyme 1 (BACE<\/jats:styled-content>1) and \u03b3\u2010secretase. Inhibition of one or both of these enzymes prevents A\u03b2 generation and the accompanying A\u03b2 accumulation. Antigen binding fragments from camelid heavy chain only antibodies (VHH<\/jats:styled-content>s) were found to exert excellent enzyme inhibition activity. In the present study, we generated VHH<\/jats:styled-content>s against BACE<\/jats:styled-content>1 by active immunization of Lama\u00a0glama<\/jats:italic> with the recombinant BACE<\/jats:styled-content>1 protein. Two classes of VHH<\/jats:styled-content>s were selected from a VHH<\/jats:styled-content>\u2010phage display library by competitive elution with a peptide encoding the Swedish mutation variant of the BACE<\/jats:styled-content>1 processing site. One VHH<\/jats:styled-content> was found to inhibit the enzyme activity of BACE<\/jats:styled-content>1 in\u00a0vitro<\/jats:italic> and in cell culture, whereas two other VHH<\/jats:styled-content>s were found to stimulate BACE<\/jats:styled-content>1 activity under the same conditions in\u00a0vitro<\/jats:italic>. Furthermore, an in\u00a0vivo<\/jats:italic> study with a transgenic AD<\/jats:styled-content> mouse model, using intracisternal injection of the inhibitory VHH<\/jats:styled-content>, led to acute reduction of the A\u03b2 load in the blood and brain. This inhibitory VHH<\/jats:styled-content> may be considered as a candidate molecule for a therapy directed towards reduction of A\u03b2 load and prevention of AD<\/jats:styled-content> progression. Both the inhibitory and stimulatory VHH<\/jats:styled-content> may be useful for improving our understanding of the structure\u2013function relationship of BACE<\/jats:styled-content>1, as well as its role in AD<\/jats:styled-content> progression.<\/jats:p><\/jats:sec>Database<\/jats:title>The GenBank sequence accession numbers are KR363186<\/jats:ext-link> for VHH B1a; KR363187<\/jats:ext-link> for VHH B3a; and KR363188<\/jats:ext-link> for VHH B5a.<\/jats:p><\/jats:sec>","DOI":"10.1111\/febs.13367","type":"journal-article","created":{"date-parts":[[2015,7,6]],"date-time":"2015-07-06T09:35:15Z","timestamp":1436175315000},"page":"3618-3631","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Camelid heavy chain only antibody fragment domain against \u03b2\u2010site of amyloid precursor protein cleaving enzyme 1 inhibits \u03b2\u2010secretase activity in\u00a0vitro<\/i> and 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