Abstract
ADAM (a disintegrin and metalloproteinase) is a family of widely expressed, transmembrane and secreted proteins of approximately 750 amino acids in length with functions in cell adhesion and proteolytic processing of the ectodomains of diverse cell-surface receptors and signaling molecules. ADAM10 is the main α-secretase that cleaves APP (amyloid precursor protein) in the non-amyloidogenic pathway inhibiting the formation of β-amyloid peptide, whose accumulation and aggregation leads to neuronal degeneration in Alzheimer’s disease (AD). ADAM10 is a membrane-anchored metalloprotease that sheds, besides APP, the ectodomain of a large variety of cell-surface proteins including cytokines, adhesion molecules and notch. APP cleavage by ADAM10 results in the production of an APP-derived fragment, sAPPα, which is neuroprotective. As increased ADAM10 activity protects the brain from β-amyloid deposition in AD, this strategy has been proved to be effective in treating neurodegenerative diseases, including AD. Here, we describe the physiological mechanisms regulating ADAM10 expression at different levels, aiming to propose strategies for AD treatment. We report in this review on the physiological regulation of ADAM10 at the transcriptional level, by epigenetic factors, miRNAs and/or translational and post-translational levels. In addition, we describe the conditions that can change ADAM10 expression in vitro and in vivo, and discuss how this knowledge may help in AD treatment. Regulation of ADAM10 is achieved by multiple mechanisms that include transcriptional, translational and post-translational strategies, which we will summarize in this review.
Highlights
ADAM is a family of transmembrane and secreted metalloproteinases comprising approximately 750 amino acids, with functions in cell adhesion and proteolytic processing of the ectodomains of diverse cell-surface receptors and signaling molecules [1].APP cleavage by ADAM10 results in the production of an APP-derived fragment, sAPPα, which is neuroprotective
It has been demonstrated that miR-144 and miR-122 can bind to ADAM10 mRNA and promote its regulation, as its superexpression caused a decrease in the levels of this protein [83]
In partial agreement with these studies, we recently showed that miR-144, -374 and -221 are downregulated in the total blood of Alzheimer’s disease (AD) subjects and ADAM10 protein levels are significantly decreased upon transient overexpression of miR-221 in SH-SY5Y cells, but not altered after overexpression of miR-144-5p and miR-374, indicating the specificity of miR-221 in the regulation of ADAM10 levels [85]
Summary
ADAM (a disintegrin and metalloproteinase) is a family of transmembrane and secreted metalloproteinases comprising approximately 750 amino acids, with functions in cell adhesion and proteolytic processing of the ectodomains of diverse cell-surface receptors and signaling molecules [1]. It has been demonstrated that vitamin A deficiency leads to an increase in Aβ peptide levels in wild-type mice, and that the rescue of this deficiency increased non-amyloidogenic APP processing in combination with an increase of ADAM10 levels [17] Another component of the RA pathway is the peroxisome proliferator-activated receptor (PPARα), as it interacts with RXR to form a heterodimeric structure that binds to RARs. PPARα is a transcription factor involved in fatty acid metabolism and it is constitutively expressed in the hippocampal neurons [18]. PPARα was demonstrated to activate ADAM10 transcription, reducing endogenous Aβ production by shifting APP processing toward the α-secretase pathway in vivo [19], showing that it is an important partner for retinoic acid to stimulate ADAM10 transcription [10] These data seem to point out that vitamin A supplementation would improve cognition and enhance AD behavioral and psychological symptoms. Whether other synthetic retinoid derivatives or therapeutic regimens will be able to increase cognitive performance in human patients remains to be seen
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