The extracellular domain of Bri2 (ITM2B) binds the ABri peptide (1–23) and amyloid β-peptide (Aβ1–40): Implications for Bri2 effects on processing of amyloid precursor protein and Aβ aggregation

In Alzheimer’s disease the amyloid β-peptide (Aβ) aggregates in brain tissue and arteries. Aβ is proteolytically cleaved out from amyloid precursor protein (APP) by different secretases. Recently, the transmembrane protein ITM2B/Bri2, which is expressed in neurons and associated with familial British and Danish dementia, was shown to inhibit APP processing in transfected cells as well as in transgenic mice. Several mechanisms by which Bri2 can interfere with Aβ production and aggregation have been proposed. Herein, we studied recombinant human Bri2 (residues 90–236) containing the extracellular Brichos domain without the ABri23 peptide. Bri2(90–236) binds to ABri23, which suggests that these two parts interact during Bri2 biosynthesis, in line with proposed functions of Brichos domains in other proteins. Moreover, Bri2(90–236) binds Aβ1–40 and inhibits its aggregation and fibril formation. These data suggest a model for how the processing of Bri2 and APP are interrelated.