UC San Diego

Amyloid precursor protein (APP) is a type one transmembrane protein and has two mammalian homologues, amyloid precursor-like protein 1 (APLP1) and amyloid precursor-like protein 2 (APLP2). APP is the parent molecule to amyloid-[beta] (A[beta]), the amyloidogenic species found in the plaques of people with Alzheimer's disease (AD). Several lines of evidence suggest A[beta] to lie at the center of AD pathology, with converging evidence to indicate that synapses are the site of the initial damage. Recent studies have shown that APP may be necessary for the toxicity induced by A[beta], in part by cleavage of a caspase site on the intracellular domain of the APP protein and the subsequent release of the toxic molecule, C31. This caspase cleavage is shown to induce APP-mediated A[beta] toxicity in cell culture models, however assays were based on contribution to cell death. Thus, the physiologic relevance of the cleavage event has never been tested and in particular, whether this pathway contributes to synaptic damage is unclear. Here, we seek to test the role of caspase cleavage of APP in A[beta]- induced synaptic damage and to test the specificity of this event by testing whether caspase cleavage of APLP2, the protein most homologous to APP, also contributes to these A[beta]-driven synaptic changes. Additionally, because APP dimerization was shown to be necessary for the Aβ-induced caspase cleavage of APP and subsequent release of C31, we wanted to test the effects of dimerization on APP proteolysis and A[beta] production