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The Journal of Neuroscience, August 27, 2008, 28(35):8668-8676; doi:10.1523/JNEUROSCI.2094-08.2008

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Development/Plasticity/Repair
BRI2 Inhibits Amyloid β-Peptide Precursor Protein Processing by Interfering with the Docking of Secretases to the Substrate

Shuji Matsuda,1 * Luca Giliberto,1 * Yukiko Matsuda,1 Eileen M. McGowan,2 and Luciano D'Adamio1,3

1Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York 10461, 2Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, Florida 32224, and 3CEINGE Biotecnologie Avanzate, Dipartimento di Biochimica e Biotecnologie Mediche, Università di Napoli Federico II, 80145 Naples, Italy

Correspondence should be addressed to Luciano D'Adamio, Albert Einstein College of Medicine, Department of Microbiology and Immunology, 1300 Morris Park Avenue, Bronx, NY 10461. Email: ldadamio{at}aecom.yu.edu

Genetic alterations of amyloid β-peptide (Aβ) production caused by mutations in the Aβ precursor protein (APP) cause familial Alzheimer's disease (AD). Mutations in BRI2, a gene of undefined function, are linked to familial British and Danish dementias, which are pathologically and clinically similar to Alzheimer's disease. We report that BRI2 is a physiological suppressor of Aβ production. BRI2 restrict docking of {gamma}-secretase to APP and access of {alpha}- and β-secretases to their cleavage APP sequences. Alterations of BRI2 by gene targeting or transgenic expression regulate Aβ levels and AD pathology in mouse models of AD. Competitive inhibition of APP processing by BRI2 may provide a new approach to AD therapy and prevention.

Key words: amyloid-β; Alzheimer's disease; BRI2; familial dementia; synaptic plasticity; mice

Received May 7, 2008; revised June 23, 2008; accepted July 17, 2008.

Correspondence should be addressed to Luciano D'Adamio, Albert Einstein College of Medicine, Department of Microbiology and Immunology, 1300 Morris Park Avenue, Bronx, NY 10461. Email: ldadamio{at}aecom.yu.edu




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S. Matsuda, Y. Matsuda, and L. D'Adamio
BRI3 Inhibits Amyloid Precursor Protein Processing in a Mechanistically Distinct Manner from Its Homologue Dementia Gene BRI2
J. Biol. Chem., June 5, 2009; 284(23): 15815 - 15825.
[Abstract] [Full Text] [PDF]


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