Dementia-related Bri2 BRICHOS is a versatile molecular chaperone that efficiently inhibits Aß42 toxicity in Drosophila.

ABSTRACT

Formation of fibrils of the amyloid-ß peptide (Aß) is suggested to play a central role in neurodegeneration in Alzheimer's disease (AD), for which no effective treatment exists. The BRICHOS domain is a part of several disease-related proproteins, the most studied ones being Bri2 associated with familial dementia and prosurfactant protein C (proSP-C) associated with lung amyloid. BRICHOS from proSP-C has been found to be an efficient inhibitor of Aß aggregation and toxicity, but its lung-specific expression makes it unsuited to target in AD. Bri2 is expressed in the brain, affects processing of Aß precursor protein, and increased levels of Bri2 are found in AD brain, but the specific role of its BRICHOS domain has not been studied in vivo Here, we find that transgenic expression of the Bri2 BRICHOS domain in the Drosophila central nervous system (CNS) or eyes efficiently inhibits Aß42 toxicity. In the presence of Bri2 BRICHOS, Aß42 is diffusely distributed throughout the mushroom bodies, a brain region involved in learning and memory, whereas Aß42 expressed alone or together with proSP-C BRICHOS forms punctuate deposits outside the mushroom bodies. Recombinant Bri2 BRICHOS domain efficiently prevents Aß42-induced reduction in γ-oscillations in hippocampal slices. Finally, Bri2 BRICHOS inhibits several steps in the Aß42 fibrillation pathway and prevents aggregation of heat-denatured proteins, indicating that it is a more versatile chaperone than proSP-C BRICHOS. These findings suggest that Bri2 BRICHOS can be a physiologically relevant chaperone for Aß in the CNS and needs to be further investigated for its potential in AD treatment.