Transmembrane proteins BRI2 and amyloid precursor protein (APP) co-localize with amyloid ␤ (A␤) lesions in sporadic Alzheimer disease and mutations in both precursor proteins are linked to early-onset familial cases of cerebral amyloidosis associated with dementia and/or cerebral hemorrhage. A specific interaction between BRI2 and APP was unveiled by immunoprecipitation experiments using transfected and non-transfected cells. The use of deletion mutants further revealed that stretches 648 -719 of APP751 and 46 -106 of BRI2, both inclusive of the full transmembrane domains, are sufficient for the interaction. Removal of most of the APP and BRI2 extracellular domains without affecting the interaction implies that both proteins interact when are expressed on the same cell membrane (cis) rather than on adjacent cells (trans). The presence of BRI2 had a modulatory effect on APP processing, specifically increasing the levels of cellular APP as well as ␤-secretasegenerated COOH-terminal fragments while decreasing the levels of ␣-secretase-generated COOH-terminal fragments as well as the secretion of total APP and A␤ peptides. Determining the precise molecular pathways affected by the specific binding between APP and BRI2 could result in the identification of common therapeutic targets for these sporadic and familial neurodegenerative disorders. A␤,1 a 39 -42-amino acid peptide of unknown biological function normally present in biological fluids, is also the main constituent of parenchymal and vascular amyloid deposits characteristic of Alzheimer disease (AD) (reviewed in Ref. 1). It is an internal fragment of the larger type-I transmembrane amyloid precursor protein APP (also referred as A␤PP), which exists in several isoforms of different length, ranging from 695 to 770 residues (2, 3). From all these APP isoforms, A␤ is normally generated by proteolytic processing through the sequential action of ␤-and ␥-secretases. Within amyloid lesions, a number of unrelated components collectively known as amyloid-associated proteins (amyloid P-component, ␣1-antichymotrypsin, apoE, apoJ, complement components, vitronectin, extracellular matrix proteins, and APP, among others) co-localize with fibrillar and non-fibrillar A␤, as shown by immunohistochemical studies (4 -10). It is not clear whether these proteins are important for the mechanism of amyloidogenesis or just innocent bystanders. Recently, it was reported that a novel protein BRI2 was abundant in dystrophic neurites, in senile plaques, and around vessels in ischemic lesions in AD and was also detected in Lewy neurites in cases of dementia with Lewy bodies and Parkinson disease (11). Of interest, mutations at or near the stop codon of BRI2 are associated with dementia and cerebellar ataxia in kindreds of British (12) and Danish (13) origin.BRI2 is a type-II transmembrane protein encoded by the single gene BRI2 (also known as ITM2B and E25B) located on the long arm of chromosome 13 (12, 14 -16). BRI2 belongs to an evolutionary conserved multigene family comprising at least...

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