Increased CSF APPs-α levels in patients with Alzheimer disease treated with acitretin

Endres, Kristina; Fahrenholz, Falk; Lotz, Johannes; Hiemke, Christoph; Teipel, Stefan J.; Lieb, Klaus; Tüscher, Oliver; Fellgiebel, Andreas

doi:10.1212/wnl.0000000000001017

Cited by 109 publications

(87 citation statements)

References 26 publications

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“…The complex expression patterns and time courses of ADAM10 and its substrates may constrain the use of ADAM10-targeting drugs to specific situations, aged patients or some diseases. A clinical pilot study using acitretin was, however, promising (Endres et al, 2014). Acitretin (Neotigason), which increases APP processing along the non-amyloidogenic pathway in vitro , in primary cells, and in AD model mice (Tippmann et al, 2009; Reinhardt et al, 2016), was given to patients with mild to moderate AD for 4 weeks.…”

Section: Conclusion and Outlook—adam10-targeting Drugs As Novel Theramentioning

confidence: 99%

Regulation of Alpha-Secretase ADAM10 In vitro and In vivo: Genetic, Epigenetic, and Protein-Based Mechanisms

Endres

Deller

2017

Front. Mol. Neurosci.

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ADAM10 (A Disintegrin and Metalloproteinase 10) has been identified as the major physiological alpha-secretase in neurons, responsible for cleaving APP in a non-amyloidogenic manner. This cleavage results in the production of a neuroprotective APP-derived fragment, APPs-alpha, and an attenuated production of neurotoxic A-beta peptides. An increase in ADAM10 activity shifts the balance of APP processing toward APPs-alpha and protects the brain from amyloid deposition and disease. Thus, increasing ADAM10 activity has been proposed an attractive target for the treatment of neurodegenerative diseases and it appears to be timely to investigate the physiological mechanisms regulating ADAM10 expression. Therefore, in this article, we will (1) review reports on the physiological regulation of ADAM10 at the transcriptional level, by epigenetic factors, miRNAs and/or protein interactions, (2) describe conditions, which change ADAM10 expression in vitro and in vivo, (3) report how neuronal ADAM10 expression may be regulated in humans, and (4) discuss how this knowledge on the physiological and pathophysiological regulation of ADAM10 may help to preserve or restore brain function.

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Section: Conclusion and Outlook—adam10-targeting Drugs As Novel Theramentioning

confidence: 99%

Regulation of Alpha-Secretase ADAM10 In vitro and In vivo: Genetic, Epigenetic, and Protein-Based Mechanisms

Endres

Deller

2017

Front. Mol. Neurosci.

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“…ADAM10 is another promising target for the treatment of AD, as demonstrated by a recent study using the synthetic retinoid acitretin to increase ADAM10 expression in AD patients (Endres et al, 2014). Targeting specific members of the TspanC8s, which enhance ADAM10 activity, but have different impact on its substrate specificity, could possibly reduce side effects of a global ADAM10 activation.…”

Section: Tetraspanins As Therapeutic Targetsmentioning

confidence: 99%

The Emerging Role of Tetraspanins in the Proteolytic Processing of the Amyloid Precursor Protein

Seipold

Säftig

2016

Front. Mol. Neurosci.

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Tetraspanins are a family of ubiquitously expressed and conserved proteins, which are characterized by four transmembrane domains and the formation of a short and a large extracellular loop (LEL). Through interaction with other tetraspanins and transmembrane proteins such as growth factors, receptors and integrins, tetraspanins build a wide ranging and membrane spanning protein network. Such tetraspanin-enriched microdomains (TEMs) contribute to the formation and stability of functional signaling complexes involved in cell activation, adhesion, motility, differentiation, and malignancy. There is increasing evidence showing that the tetraspanins also regulate the proteolysis of the amyloid precursor protein (APP) by physically interacting with the APP secretases. CD9, CD63, CD81, Tspan12, Tspan15 are among the tetraspanins involved in the intracellular transport and in the stabilization of the gamma secretase complex or ADAM10 as the major APP alpha secretase. They also directly regulate, most likely in concert with other tetraspanins, the proteolytic function of these membrane embedded enzymes. Despite the knowledge about the interaction of tetraspanins with the secretases not much is known about their physiological role, their importance in Alzheimer's Disease and their exact mode of action. This review aims to summarize the current knowledge and open questions regarding the biology of tetraspanins and the understanding how these proteins interact with APP processing pathways. Ultimately, it will be of interest if tetraspanins are suitable targets for future therapeutical approaches.

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“…Thus, the increased sheddase activity of ADAM10⌬cyto and the two mutants that affect the ER retention motif compared with the ADAM10 WT indicates that the intracellular domain of ADAM10 functions as a negative regulator of its constitutive sheddase activity by limiting the exit of ADAM10 from the ER. Targeting this ER retention motif could thus represent an attractive means to modulate the activity of ADAM10, which has been shown to function as a protective ␣-secretase in the context of Alzheimer's disease (27)(28)(29)(30).…”

Section: Discussionmentioning

confidence: 99%

The Cytoplasmic Domain of A Disintegrin and Metalloproteinase 10 (ADAM10) Regulates Its Constitutive Activity but Is Dispensable for Stimulated ADAM10-dependent Shedding

Maretzky

Evers

Gall

et al. 2015

Journal of Biological Chemistry

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Background: Release of membrane proteins from the cell surface by the metalloproteinase ADAM10 is post-translationally regulated. Results:The cytoplasmic domain of ADAM10 negatively controls its constitutive activity but is dispensable for its stimulation. Conclusion: Post-translational stimulation of ADAM10 requires its transmembrane and/or extracellular domain. Significance: Elucidating the regulation of ADAM10 is crucial for understanding the control of ADAM10-dependent cell surface proteolysis.

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Increased CSF APPs-α levels in patients with Alzheimer disease treated with acitretin

Abstract: This study provides Class III evidence that in patients with AD, oral acitretin increases CSF APPs-α levels.

Cited by 109 publications

References 26 publications

Regulation of Alpha-Secretase ADAM10 In vitro and In vivo: Genetic, Epigenetic, and Protein-Based Mechanisms

Regulation of Alpha-Secretase ADAM10 In vitro and In vivo: Genetic, Epigenetic, and Protein-Based Mechanisms

The Emerging Role of Tetraspanins in the Proteolytic Processing of the Amyloid Precursor Protein

The Cytoplasmic Domain of A Disintegrin and Metalloproteinase 10 (ADAM10) Regulates Its Constitutive Activity but Is Dispensable for Stimulated ADAM10-dependent Shedding

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