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The Journal of Neuroscience, June 4, 2008, 28(23):6030-6036; doi:10.1523/JNEUROSCI.0891-08.2008

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Neurobiology of Disease
BRI2 (ITM2b) Inhibits Aβ Deposition In Vivo

Jungsu Kim,¹ Victor M. Miller,¹ Yona Levites,¹ Karen Jansen West,¹ Craig W. Zwizinski,¹ Brenda D. Moore,¹ Fredrick J. Troendle,¹ Maralyssa Bann,¹ Christophe Verbeeck,¹ Robert W. Price,¹ Lisa Smithson,¹ Leilani Sonoda,¹ Kayleigh Wagg,¹ Vijayaraghavan Rangachari,¹ Fanggeng Zou,¹ Steven G. Younkin,¹ Neill Graff-Radford,² Dennis Dickson,¹ Terrone Rosenberry,¹ and Todd E. Golde¹

Departments of ¹Neuroscience and ²Neurology, Mayo Clinic College of Medicine, Mayo Clinic Jacksonville, Jacksonville, Florida 32224

Correspondence should be addressed to either Terrone Rosenberry (regarding Aβ/Bri2-23 aggregation studies) or Todd E. Golde (all other correspondence), Department of Neuroscience, Mayo Clinic College of Medicine, Mayo Clinic Jacksonville, 4500 San Pablo Road, Jacksonville, FL 32224, Email: rosenberry{at}mayo.edu or Email: tgolde{at}mayo.edu

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 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 aa peptide, Bri23, released from BRI2 by normal processing, is present in human 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.

Key words: BRI2; ITM2b; amyloid β protein; Alzheimer's disease; somatic brain transgenesis; adeno-associated virus

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Received Feb. 28, 2008; revised May 2, 2008; accepted May 4, 2008.

Correspondence should be addressed to either Terrone Rosenberry (regarding Aβ/Bri2-23 aggregation studies) or Todd E. Golde (all other correspondence), Department of Neuroscience, Mayo Clinic College of Medicine, Mayo Clinic Jacksonville, 4500 San Pablo Road, Jacksonville, FL 32224, Email: rosenberry{at}mayo.edu or Email: tgolde{at}mayo.edu

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