tailieunhanh - Báo cáo khoa học: Upregulation of the a-secretase ADAM10 – risk or reason for hope?

A decade ago, a disintegrin and metalloproteinase 10 (ADAM10) was iden-tified as ana-secretase and as a key proteinase in the processing of the amy-loid precursor protein. Accordingly, the important role that it plays in Alzheimer’s disease was manifested. Animal models with an overexpression of ADAM10 revealed a beneficial profile of the metalloproteinase with respect to learning and memory, plaque load and synaptogenesis. | ỊFEBS Journal REVIEW ARTICLE Upregulation of the a-secretase ADAM10 - risk or reason for hope Kristina Endres and Falk Fahrenholz Department of Psychiatry and Psychotherapy ClinicalResearch Group Johannes Gutenberg-University Mainz Germany Keywords alpha-secretase amyloid precursor protein Alzheimer s disease domain structure neuroprotection shedding synaptogenesis TACE Correspondence K. Endres and F. Fahrenholz Department of Psychiatry and Psychotherapy Clinical Research Group Johannes Gutenberg-University 55131 Mainz Germany Fax 49 6131 176690 Tel 49 6131 172133 E-mail endres_k@. fahrenho@ Received 4 November 2009 revised 10 December 2009 accepted 6 January 2010 doi A decade ago a disintegrin and metalloproteinase 10 ADAM10 was identified as an a-secretase and as a key proteinase in the processing of the amyloid precursor protein. Accordingly the important role that it plays in Alzheimer s disease was manifested. Animal models with an overexpression of ADAM10 revealed a beneficial profile of the metalloproteinase with respect to learning and memory plaque load and synaptogenesis. Therefore ADAM10 presents a worthwhile target with respect to the treatment of a neurodegenerative disease such as Morbus Alzheimer. Initially ADAM10 was suggested to be an enzyme shaping the extracellular matrix by cleavage of collagen type IV or to be a tumour necrosis factor a convertase. In a relatively short time a wide variety of additional substrates with amyloid precursor protein probably being the most prominent has been identified and the search is still ongoing. Hence any side effects concerning the therapeutic enhancement of ADAM10 a-secretase activity have to be considered. The present review summarizes our knowledge about the structure and function of ADAM10 and highlights the opportunities for enhancing the expression and or activity of the a-secretase as a therapeutic target. Identification of .