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J. Biol. Chem., Vol. 280, Issue 32, 28912-28916, August 12, 2005

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The Familial Dementia BRI2 Gene Binds the Alzheimer Gene Amyloid- Precursor Protein and Inhibits Amyloid- Production^*

Shuji Matsuda, Luca Giliberto, Yukiko Matsuda, Peter Davies, Eileen McGowan, Fiona Pickford, Jorge Ghiso¶, Blas Frangione¶, and Luciano D'Adamio||

From the Albert Einstein College of Medicine, Bronx, New York 10461, the Mayo Clinic, Jacksonville, Florida 32224, and the ^¶New York University School of Medicine, New York, New York 10016

Alzheimer disease (AD), the most common senile dementia, is characterized by amyloid plaques, vascular amyloid, neurofibrillary tangles, and progressive neurodegeneration. Amyloid is mainly composed by amyloid- (A) peptides, which are derive from processing of the -amyloid precursor protein (APP), better named amyloid- precursor protein (APP), by secretases. The APP intracellular domain (AID), which is released together with A, has signaling function, since it modulates apoptosis and transcription. Despite its biological and pathological importance, the mechanisms regulating APP processing are poorly understood. As cleavage of other -secretase substrates is regulated by membrane bound proteins, we have postulated the existence of integral membrane proteins that bind APP and regulate its processing. Here, we show that BRI2, a type II membrane protein, interacts with APP. Interestingly, 17 amino acids corresponding to the NH₂-terminal portion of A are necessary for this interaction. Moreover, BRI2 expression regulates APP processing resulting in reduced A and AID levels. Altogether, these findings characterize the BRI2-APP interaction as a regulatory mechanism of APP processing that inhibits A production. Notably, BRI2 mutations cause familial British (FBD) and Danish dementias (FDD) that are clinically and pathologically similar to AD. Finding that BRI2 pathogenic mutations alter the regulatory function of BRI2 on APP processing would define dysregulation of APP cleavage as a pathogenic mechanism common to AD, FDD, and FBD.

Received for publication, May 23, 2005 , and in revised form, June 14, 2005.

^* This work was supported in part by Alzheimer Disease Research Grant A2003-076; National Institutes of Health Grants RO1 AG22024 and RO1 AG21588 (to L. D.), RO1 AG08721, RO1 AG05891, and RO1 NS38777 (to B. F.), and RO1 AG022595 (to E. M.); and by the Alzheimer Association (to J. G.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^|| To whom correspondence should be addressed. Tel.: 718-430-3244 (or 3245); E-mail: ldadamio{at}aecom.yu.edu.

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