The Bri2 and Bri3 BRICHOS Domains Interact Differently with Aß42 and Alzheimer Amyloid Plaques.

Alzheimer's disease (AD) is the most common form of dementia and there is no successful treatment available. Evidence suggests that fibril formation of the amyloid ß-peptide (Aß) is a major underlying cause of AD, and treatment strategies that reduce the toxic effects of Aß amyloid are sought for. The BRICHOS domain is found in several proteins, including Bri2 (also called integral membrane protein 2B (ITM2B)), mutants of which are associated with amyloid and neurodegeneration, and Bri3 (ITM2C). We have used mouse hippocampal neurons and brain tissues from mice and humans and show Bri3 deposits dispersed on AD plaques. In contrast to what has been shown for Bri2, Bri3 immunoreactivity is decreased in AD brain homogenates compared to controls. Both Bri2 and Bri3 BRICHOS domains interact with Aß40 and Aß42 present in neurons and reduce Aß42 amyloid fibril formation in vitro, but Bri3 BRICHOS is less efficient. These results indicate that Bri2 and Bri3 BRICHOS have different roles in relation to Aß aggregation.