Title: α-Secretase Activation – An Approach to Alzheimer’s Disease Therapy
Abstract: The nonamyloidogenic pathway of processing the amyloid precursor protein (APP) involves the cleavage within the amyloid-β peptide sequence, and thus precludes amyloid-β formation. The identification of a member of the disintegrin and metalloproteinase family, ADAM10, as an α-secretase that prevents plaque formation and hippocampal deficits in vivo gave us the possibility to examine the α-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 α-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 α-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 α-secretase cleavage of the two substrates. Other approaches for enhancing α-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.
Publication Year: 2006
Publication Date: 2006-01-01
Language: en
Type: review
Indexed In: ['crossref', 'pubmed']
Access and Citation
Cited By Count: 59
AI Researcher Chatbot
Get quick answers to your questions about the article from our AI researcher chatbot