Alpha-secretase activation--an approach to Alzheimer's disease therapy.
The nonamyloidogenic pathway of processing the amyloid precursor protein (APP) involves the cleavage within the amyloid-beta peptide sequence, and thus precludes amyloid-beta formation. The identification of a member of the disintegrin and metalloproteinase family, ADAM10, as an alpha-secretase that prevents plaque formation and hippocampal deficits in vivo gave us the possibility to examine the alpha-secretase as a potential target for the therapy of Alzheimer's disease. Within the priority program Cellular Mechanisms of Alzheimer's Disease, we investigated several approaches to stimulate the alpha-secretase pathway. Two protein convertases were found to be responsible for the removal of the prodomain, and for the formation of the mature enzyme with alpha-secretase activity. The cloning and characterization of the human ADAM10 promoter provided the basis to examine ADAM10 gene expression. We found a common upregulation of ADAM10, APP, and APP-like protein 2 during differentiation of neuronal cells by retinoic acid, and increased alpha-secretase cleavage of the two substrates. Other approaches for enhancing alpha-secretase activity are the reduction of cellular cholesterol and the stimulation of G protein-coupled neuropeptide receptors. Our results suggest medications and dietary regiments which enhance the nonamyloidogenic pathway of APP processing to be a valuable approach to Alzheimer's disease therapy.
Fahrenholz
Falk
F
Institute of Biochemistry, University of Mainz, Mainz, Germany. bio.chemie@uni-mainz.de
Postina
Rolf
R
D000544:Alzheimer Disease / Q000188:drug therapy / Q000201:enzymology*; D053829:Amyloid Precursor Protein Secretases / Q000187:drug effects / Q000502:physiology*; D000818:Animals; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology*; D006801:Humans
D053829:Amyloid Precursor Protein Secretases