Retinoids as a perspective in treatment of Alzheimer's disease.
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).


CONCLUSIONS
Nontoxic synthetic retinoids - like acitretin - offer a valuable therapeutic approach in treatment of AD by moderately enhancing ADAM10 gene expression.
Fahrenholz
Falk
F
Institute of Biochemistry, Johannes Gutenberg-University, Mainz, Germany.
Tippmann
Frank
F
Endres
Kristina
K
D051722:ADAM Proteins / Q000235:genetics / Q000378:metabolism*; D000072197:ADAM10 Protein; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D045744:Cell Line, Tumor; D002867:Chromones / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009025:Morpholines / Q000494:pharmacology; D009447:Neuroblastoma / Q000473:pathology; D012176:Retinoids / Q000737:chemistry / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D013729:Terpenes / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects*; D014815:Vitamins / Q000737:chemistry / Q000494:pharmacology*
D002867:Chromones; D004791:Enzyme Inhibitors; D008565:Membrane Proteins; D009025:Morpholines; D012176:Retinoids; D013729:Terpenes; D014815:Vitamins; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C045673:manoalide; D053829:Amyloid Precursor Protein Secretases; D051722:ADAM Proteins; D000072197:ADAM10 Protein; C491236:ADAM10 protein, human