tailieunhanh - Báo cáo khoa học: The effects of a-secretase ADAM10 on the proteolysis of neuregulin-1

Although ADAM10 is a majora-secretase involved in non-amyloidogenic processing of the amyloid precursor protein, several additional substrates have been identified, most of them in vitro. Thus, therapeutical approaches for the prevention of Alzheimer’s disease by upregulation of this metalloproteinase may have severe side effects. | The effects of a-secretase ADAM10 on the proteolysis of neuregulin-1 Christian Freese1 Alistair N. Garratt2 Falk Fahrenholz1 and Kristina Endres1 1 Institute of Biochemistry Johannes Gutenberg-University Mainz Germany 2 Department of Neurosciences Max-Delbruck-Centre Berlin Germany Keywords Alzheimer ErbB metalloproteinase myelination shedding Correspondence K. Endres Institute of Biochemistry Johannes Gutenberg-University Johann-Joachim-Becherweg 30 55128 Mainz Germany Fax 49 6131 3925348 Tel 49 6131 3926182 E-mail endres@ Present address Institute of Pathology Johannes Gutenberg-University Mainz Germany Received 28 August 2008 revised 22 December 2008 accepted 6 January 2009 doi Although ADAM10 is a major a-secretase involved in non-amyloidogenic processing of the amyloid precursor protein several additional substrates have been identified most of them in vitro. Thus therapeutical approaches for the prevention of Alzheimer s disease by upregulation of this metalloproteinase may have severe side effects. In the present study we examined whether the ErbB receptor ligand neuregulin-1 which is essential for myelination and other important neuronal functions is cleaved by ADAM10. Studies with b- and y-secretase inhibitors as well as with the metalloproteinase inhibitor GM6001 revealed an inhibition of neuregulin-1 processing in human astroglioma cell line U373 however specific RNA interference-induced knockdown of ADAM10 remained without effect. In vivo investigations of mice overexpressing either ADAM10 or dominant negative ADAM10 showed unaltered cleavage of neuregulin-1 compared to wild-type animals. As a consequence the myelin sheath thickness of peripheral nerves was unaffected in mice with altered ADAM10 activity. Thus although the b-secretase BACE-1 acts as a neuregulin-1 sheddase ADAM10 does not lead to altered neuregulin-1 processing either in cell culture or in vivo. Adverse reactions of an ADAM10-based therapy of