BRI2 (ITM2b) Inhibits Aβ Deposition in Vivo

Jungsu Kim, Mayo Clinic College of Medicine
Victor M. Miller, Mayo Clinic College of Medicine
Yona Levites, Mayo Clinic College of Medicine
Karen Jansen West, Mayo Clinic College of Medicine
Craig W. Zwizinski, Mayo Clinic College of Medicine
Brenda D. Moore, Mayo Clinic College of Medicine
Frederick J. Troendle, Mayo Clinic College of Medicine
Maralyssa Bann, Mayo Clinic College of Medicine
Christophe Verbeeck, Mayo Clinic College of Medicine
Robert W. Price, Mayo Clinic College of Medinice
Lisa Smithson, Mayo Clinic College of Medicine
Leilani Sonoda, Mayo Clinic College of Medicine
Kayleigh Wagg, Mayo Clinic College of Medicine
Vijayaraghavan Rangachari, University of Southern Mississippi
Fanggeng Zou, Mayo Clinic College of Medicine
Steven G. Younkin, Mayo Clinic College of Medicine
Neill Graff-Radford, Mayo Clinic College of Medicine
Dennis Dickson, Mayo Clinic College of Medicine
Terrone Roseberry, Mayo Clinic College of Medicine
Todd E. Golde, Mayo Clinic College of Medicine

Originally published in Journal of Neuroscience. 2008 June 4; 28(23): 6030–6036

Abstract

Analyses of the biologic effects of mutations in the BRI2 (ITM2b) and the amyloid β precursor protein (APP) genes support the hypothesis that cerebral accumulation of amyloidogenic peptides in familial British and familial Danish dementias and Alzheimer’s disease (AD) is associated with neurodegeneration. We have used somatic brain transgenic technology to express the BRI2 and BRI2-Aβ1-40 transgenes in amyloid β protein precursor (APP) mouse models. Expression of BRI2-Aβ1-40 mimics the suppressive effect previously observed using conventional transgenic methods, further validating the somatic brain transgenic methodology. Unexpectedly, we also find that expression of wild type human BRI2 reduces cerebral Aβ deposition in an AD mouse model. Additional data indicate that the 23 amino acid peptide, Bri23, released from BRI2 by normal processing is present in human cerebrospinal fluid (CSF), inhibits Aβ aggregation in vitro, and mediates its anti-amyloidogenic effect in vivo. These studies demonstrate that BRI2 is a novel mediator of Aβ deposition in vivo.