Upregulation of the alpha-secretase ADAM10--risk or reason for hope?
A decade ago, a disintegrin and metalloproteinase 10 (ADAM10) was identified as an alpha-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 alpha 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 alpha-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 alpha-secretase as a therapeutic target.
Endres
Kristina
K
Department of Psychiatry and Psychotherapy, Clinical Research Group, Johannes Gutenberg-University, Mainz, Germany. endres_k@psychiatrie.klinik.uni-mainz.de
Fahrenholz
Falk
F
D051722:ADAM Proteins / Q000096:biosynthesis*; D000072197:ADAM10 Protein; D000544:Alzheimer Disease / Q000378:metabolism; D053829:Amyloid Precursor Protein Secretases / Q000096:biosynthesis* / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000737:chemistry; D000818:Animals; D024141:Collagen Type IV / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D008565:Membrane Proteins / Q000096:biosynthesis*; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D019636:Neurodegenerative Diseases / Q000378:metabolism; D017434:Protein Structure, Tertiary; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D016564:Amyloid beta-Protein Precursor; D024141:Collagen Type IV; D008565:Membrane Proteins; D014409:Tumor Necrosis Factor-alpha; D053829:Amyloid Precursor Protein Secretases; D051722:ADAM Proteins; D000072197:ADAM10 Protein; C491236:ADAM10 protein, human