REGULATION OF ALZHEIMER’S GENE APP PROCESSING BY FAMILIAL DEMENTIA GENE BRI2

Alzheimer’s disease (AD) is the most common cause of dementia in the world. It is estimated that about 1% of humans aged 60-64 years have AD, increasing steadily to as many as 35-40% after age 85. AD pathogenesis is firmly associated with the cleavage of a protein, named APP, present on the cell surface. This is demonstrated by the fact that mutations in APP or in other proteins responsible for its cleavage cause familial forms of Alzheimer’s disease, these forms accounting for more than 10% of the cases of AD. Thus, because of its biological and pathological importance, understanding how APP cleavage is controlled is of great relevance. Based on the analogy between APP and another cell surface protein, Notch, we have postulated the existence of proteins that can bind APP, regulating its cleavage. We have recently identified as a putative APP interacting protein a protein, named BRI2, already described as mutated in patients with two disease clinically and pathologically similar to AD, the Familial British and Danish dementia (FBD and FDD) syndromes. Remarkably, we have preliminary date showing that BRI2 inhibits APP cleavage. The objectives of our work will be to determine whether BRI2 regulates and/or modifies AD pathogenesis and progression and whether the two BRI2 mutants that cause FBD and FDD are less potent inhibitors of APP cleavage. The outputs of our work will be several. The definition of a role for BRI2 as inhibitor of APP cleavage will not only provide novel information on the molecular mechanisms of AD, FBD and FDD pathogenesis but will be also therapeutically relevant. In fact, compound capable of either mimicking or enhancing the inhibitory function of BRI2 on APP cleavage could be effective AD drugs.