Role of Fibulin-1 in APP Processing

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DESCRIPTION (provided by applicant): Many current pharmacological approaches to combating Alzheimer's disease (AD) seek to block A� production through inhibition of the amyloidogenic enzymes known as �- and ?-secretases. An alternative approach is to activate the �-secretase processing of amyloid precursor protein (APP), which is mediated by several members of the disintegrin family of metalloproteases, ADAM9, ADAM10 and ADAM17. Processing of APP by these �-secretases is thought to be beneficial with respect to AD since it limits production of A� and generates the neuroprotective soluble APP� (sAPP�) product. Fibulin-1 (Fbln1) is an extracellular matrix protein, expressed in the brain by neurons, that binds the amino terminus of APP and sAPP�. The significance of this interaction is not yet established however, we have found that Fbln1 also binds to other membrane anchored �-secretase substrates, heparin binding-epidermal growth factor (HB-EGF) and neuregulin-1 (NRG1). We also show that Fbln1 acts to inhibit the proteolytic release of soluble forms of HB-EGF and NRG1. Furthermore, we have found increased levels of sAPP� in the conditioned culture medium of Fbln1 null mouse embryo fibroblasts (MEFs) as compared to wildtype MEFs. Based on these findings it is hypothesized that Fbln1 serves as an inhibitor of �-secretase processing of APP and therefore may represent a therapeutic target that if inhibited might lead to augmented �-secretase processing of APP and reduced pathological APP cleavage. To address this hypothesis there are three specific aims: 1) Determine whether brain APP proteolytic cleavage is altered in Fbln1-deficient mice, 2) determine whether transgenic overexpression of Fbln1 accelerates A� production and exacerbates AD pathogenesis, and 3) determine whether Fbln1 inhibits �-secretase processing of APP in cultured cells.