Alzheimer's disease (AD) pathogenesis is firmly associated with the processing of the amyloid precursor protein (APP), since mutations in APP or in the enzymes responsible for its processing cause Familial Alzheimer's disease. Because of its biological and pathological importance, understanding how APP cleavage is controlled is of great relevance. Inhibition of APP processing may possibly hold the solution for therapeutic intervention in AD. We postulated the existence of membrane proteins that bind APP and regulate its processing and have identified BRI2 as an APP ligand. Of note, BRI2 mutations cause Familial British and Danish Dementia (FBD and FDD), two AD-like neurodegenerative disorders. Mature BRI2 inhibits APP processing and A2 production and, interestingly, BRI2 mutants that cause FDD have a defect in maturation. These findings prompted us to hypothesize that BRI2 regulates and/or modifies AD pathogenesis and that BRI2 FDD mutants are ineffective inhibitors of A2 generation in vivo. This last point hints to the possibility that dis-regulation of APP processing may participate in the pathogenesis of FDD and FBD. To test these hypothesis, we have created Bri2-null mice, and a mouse knock-in (KI) models of FDD (FDDKI), which is genetically congruous, carrying one wild-type and one mutant Bri2 allele, to the human cases. Our data shows that FDDKI mice have an impairment in synaptic plasticity and severe hippocampal memory deficits. Recovery from these defects is seen in FDDKI mice haplodeficient for APP. Bri2 heterozygous mice show similar memory and synaptic plasticity defects as FDDKI mice, leading us to believe this is a loss of function mutation, with the function lost being the inhibition of processing of APP by BRI2. We have also found that a BRI2-drived peptide binds and inhibits APP processing specifically, and can rescue the synaptic deficits found in the FDDKI and a popular transgenic mouse model of AD (APPtg2575). Here, we hope to further characterize the synaptic and hippocampal memory deficits in FDDKI and Bri2 heterozygous mice to shed light on the pathogenesis of AD, as well as test the Bri2-derived peptide in vivo as a possible therapeutic intervention for AD.
BRI2 regulates APP processing without affecting the activity of either 2-, 1- or 3-secretases. Our preliminary data indicate that pathogenic BRI2 mutations, which cause familial dementias similar to AD, reduce the anti-APP processing activity of BRI2. This leads to hippocampal and synaptic plasticity defects through a loss of Bri2 function in our mice. In this application: 1) We will continue confirming that FDD is caused by a loss if BRI2 function (the function being the inhibition of APP processing). 2) We will study mechanisms that cause the memory and synaptic plasticity deficits in the FDDKI and Bri2 mice. 3) We will see if we can use a Bri2-derived peptide as a therapeutic approach in treating the memory deficits found in mouse models of dementias. The FDDKI mice are the only models of dementia genetically congruous to the human diseases. Because of their genetic fidelity with the human pathologies, FDDKI mice are instrumental in both dissecting the pathogenic mechanisms and testing therapies for human dementias, including AD. In addition, dissecting the physiological and pathological role of BRI2 and its relationship to the APP processing inhibitory activity would validate the development of compounds targeting BRI2 and capable of reducing APP processing. These compounds (e.g. N3-2A) would be specific (and effective) AD drugs that would reduce APP processing without interfering with either 2- or 3-secretase activity on other substrates. On the contrary, secretase inhibitors block cleavage of all substrates of secretases, thereby exerting toxic effects that may limit their therapeutic usefulness. This is a pressing problem since secretases have many biologically important substrates. Thus, studying the effectiveness of N3-2A in alleviating the memory deficits in mouse models of dementias could be of great importance in a therapeutic intervention to AD and other dementias.