"With life expectancy increasing rapidly in our Western world, Alzheimer’s disease (AD), a progressive neurodegenerative disorder resulting in dementia, is becoming more common, however no cures or effective treatments are currently available. The neurotoxic amyloid-β (Aβ) peptide appears central to AD pathogenesis, and is generated by β- and γ-cleavage of the larger amyloid precursor protein (APP). APP can also be cleaved by α-secretase, which cleaves within the Aβ peptide region and hence precludes the generation of Aβ. To date, the exact nature of α-secretase in the brain remains unknown, although ADAM10 (A Disintegrin And Metalloproteinase) seems to be the most likely candidate. This proposal is designed to determine definitively whether ADAM10 comprises indeed neuronal α-secretase activity in vivo, and to determine which factors regulate its activity. Using human APP (hAPP) transgenic mice deficient in neuronal ADAM10 expression we will determine whether levels of α-cleaved APP are down- and Aβ upregulated, whether this results in increased Aβ deposition and neurodegeneration, and whether ADAM10 is involved in learning and memory. Using neuronal cell culture we will determine whether growth and neuroprotective factors induce ADAM10 expression. In addition we will set up a screening system that will be used to identify molecules that regulate ADAM10 expression. These experiments will further our understanding of α-secretase in the brain and will aid in the development of novel therapies for AD."