Processing of the amyloid precursor protein (APP) is firmly associated with the pathogenesis of Alzheimer's disease (AD). In fact, mutations in APP itself and in two subunits of an enzyme that regulates APP processing, PSEN1 and PSEN2, cause Familial Alzheimer's disease (FAD). New evidence from our laboratory further stress this link between APP processing and dementia. Familial Danish Dementia (FDD), an AD-like neurodegenerative disorders, is due to mutation in the BRI2/ITM2b gene. Interestingly, BRI2 is an inhibitor of APP processing. The mutations causing FDD results in a loss of BRI2 function and increased processing of APP. Analysis of an animal model of FDD genetically congruous to the human disease (called FDDKI, which, like the human cases, carries one wild-type and one mutant Bri2 allele), shows that the FDD mutation in BRI2 causes impairment in synaptic plasticity and severe hippocampal memory deficits. Recovery from these defects is seen in FDDKI/APP haplodeficient mice. In addition, inhibition of APP processing rescues the synaptic deficits of FDDKI mice, further connecting APP processing and Familial Danish dementia. Interestingly, our preliminary data suggest that, contrary to the current dogma driving the research in dementia, sAPP and/or -CTF rather than A, are the main toxic APP metabolites. If confirmed, this view would represent a significant conceptual change for the field. Here, we will further characterize the mechanisms by which the Danish BRI2 mutation and APP processing trigger synaptic and hippocampal memory deficits in FDDKI. These studies are likely to shed light on the pathogenesis of AD, as well as to unveil novel targets for disease-modifying AD drugs. PUBLIC HEALTH RELEVANCE: Mutations in genes that regulate the processing of APP cause Familial Dementias in humans. BRI2 is one of these genes. We have generated a mouse model that faithfully represents the human dementias caused by the mutation in BRI2. In this model APP processing is increased and causes memory loss. Given the fact that these mice reproduce accurately the genetic defects of patients, they are ideal to dissect the pathogenic mechanisms that cause dementia in humans. Therefore, this model is suitable for testing therapies for human dementias, including Alzheimer's disease. The studies proposed in this grant application will also serve as a conceptual foundation to development BRI2-like drugs that reduce APP processing without inhibiting the enzymes that mediate processing of APP.