Background: In the past, we demonstrated that the disintegrin metalloproteinase ADAM10 has alpha-secretase activity in vitro and in cultured cells. We also found out that moderate overexpression of this proteinase inhibits Abeta peptide production and prevents the formation of amyloid plaques in an Alzheimer's disease (AD) mouse model. Moreover, it corrects early hippocampal defects like LTP impairment and increases cortical synaptogenesis.
Objective: Upregulation of ADAM10 might be an alternative approach concerning AD therapy. Our current research therefore focuses on substances and/or pathways which regulate ADAM10 gene expression.
Methods: Analyses of ADAM10 promoter activity were performed in human and murine neuroblastoma cell lines and important findings were validated in an AD mouse model.
Results: The outcome of our investigations indicates that a heterodimeric retinoid receptor mediates the activation of the ADAM10 promoter by all-trans-retinoic acid. This then results in enhanced ADAM10 expression, pronounced APPs-alpha secretion and diminished proteolytic processing products of the amyloidogenic pathway (APPs-beta, Abeta).
Conclusion: Nontoxic synthetic retinoids - like acitretin - offer a valuable therapeutic approach in treatment of AD by moderately enhancing ADAM10 gene expression.
Copyright 2010 S. Karger AG, Basel.