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Reticular hyperpigmentation
Published in Dimitris Rigopoulos, Alexander C. Katoulis, Hyperpigmentation, 2017
Alexander C. Katoulis, Efthymia Soura
RAK is a rare genodermatosis that is inherited in an autosomal dominant manner, and is caused by mutations on the ADAM10 gene, mapped on chromosome 15q21.3.77 The exact incidence of the condition is unknown. In general, cases have been reported in association with most ethnic backgrounds; however, the vast majority of patients are of Japanese origin.77 A number of authors have suggested that RAK should be considered a variant of DDD; however, this remains highly controversial, as the two disorders are caused by different gene mutations and exhibit distinct phenotypes. In RAK, loss-of-function mutations in ADAM10 are commonly observed.77 The ADAMs are considered a new gene family that belong to the zinc protease superfamily.78,79 More specifically, ADAM10 has been shown to play a role in the ectodomain shedding of various substrates in the skin, such as the L1 cell adhesion molecule (L1-CAM), CD44, E-cadherin, N-cadherin, IL-6R, and CD30.80 At this point, the exact pathogenetic mechanism of RAK is not well understood, but ADAM10 haploinsufficiency was recently reported to cause freckle-like macules in specific murine models.81
Pharmacology of Withanolide A
Published in Amritpal Singh Saroya, Contemporary Phytomedicines, 2017
Withanolide A and asiatic acid were investigated for their potential activities against multiple targets associated with Abeta pathways (BACE1, ADAM10, IDE, and NEP). BACE1 is a rate-limiting enzyme in the production of Abeta from amyloidbeta precursor protein (AbetaPP), while ADAM10 is involved in non-amyloidogenic processing of AbetaPP. IDE and NEP are two of the prominent enzymes involved in effectively degrading Abeta.
Ageing, Neurodegeneration and Alzheimer's Disease
Published in James N. Cobley, Gareth W. Davison, Oxidative Eustress in Exercise Physiology, 2022
Richard J. Elsworthy, Sarah Aldred
The identification of a small peptide named Aβ as the major constituent of the extracellular plaques was a driving factor in the development of the ‘Amyloid-Cascade Hypothesis’, which placed Aβ at the centre of AD research (Hardy and Higgins, 1992). This was supported by evidence of neighbouring neuritic and glial cytopathology in regions associated with memory and cognition near Aβ deposits (Selkoe and Hardy, 2016). Further, mutations within and close to the Aβ region in the APP gene are associated with aggressive autosomal dominant forms of familial AD (fAD) (Hunter and Brayne, 2018). The most common cause of fAD is missense mutations to the PSEN1 and PSEN2 genes, which are known to impact the catalytic subunit of the γ-secretase enzyme (Kelleher and Shen, 2017). γ-Secretase is responsible for a critical step in Aβ generation following beta amyloid cleaving enzyme-1 (BACE-1) cleavage of the amyloid-β precursor protein (AβPP). In many cases, PSEN1/2 mutations increase Aβ production or increase the ratio of the longer Aβ1–42 to the more physiological Aβ1–40 peptide (Sun et al., 2017). Aβ1–42 can more rapidly aggregate at lipid membranes and form oligomeric Aβ species. These oligomers accumulate in endocytotic vesicles, and thus, an increase in the Aβ1–42:Aβ1–40 ratio has been linked to AD development (Zheng et al., 2017). Aβ1–42 has been shown to more easily propagate from smaller tetra- and hexameric oligomers to larger aggregates when compared to more resistant Aβ1–40 tetramers (Bernstein et al., 2009). The appearance of such ‘intermediate’ oligomeric forms of Aβ that are particularly toxic to neurons has provided a new area of investigation for the role of Aβ in the pathology of AD (Kim et al., 2003; Lesné et al., 2008). Further, Aβ oligomers have also been shown to diffuse from Aβ fibrillar plaques (Koffie et al., 2009) and exert cytotoxic effects which are associated with synapse loss and cognitive decline (Pickett et al., 2016). The processing of AβPP is not limited to BACE-1 cleavage and can be initiated by the enzyme ‘a disintegrin and metalloproteinase-10’ (ADAM10) (Kuhn et al., 2010) (Figure 16.1). ADAM10 cleavage of AβPP cuts through the Aβ-region and leads to shedding of soluble AβPPα. The sequential cleavage by γ-secretase releases a truncated p3 peptide, thus preventing the generation of Aβ (Kuhn et al., 2010). In AD, the expression and activity of ADAM10 are lower, which may increase the proteolytic processing of AβPP by BACE-1 and thus increase Aβ generation. Further, the soluble fragment AβPPα plays a role in neurogenesis, maintaining synaptic function and supporting the formation of neuronal networks (Kögel et al., 2012; Yuan et al., 2017), and is considered neuroprotective. Missense mutations to the ADAM10 gene affecting the cysteine switch in the prodomain of the translated enzyme are also associated with an increased risk of AD (Kim et al., 2009). All of this evidence provides significant data for a role of Aβ in the progression of AD.
Trophectoderm non-coding RNAs reflect the higher metabolic and more invasive properties of young maternal age blastocysts
Published in Systems Biology in Reproductive Medicine, 2023
Panagiotis Ntostis, Grace Swanson, Georgia Kokkali, David Iles, John Huntriss, Agni Pantou, Maria Tzetis, Konstantinos Pantos, Helen M. Picton, Stephen A. Krawetz, David Miller
TSPAN15 is an essential subunit of the ADAM10 scissor complex, which is also important for early embryo development (Koo et al. 2020). The lncRNA TSPAN15 (NR_147091) was expressed approximately 6.5 times more in the YMA/rba-YMA than in the AMA/rba-AMA blastocysts. ADAM10 is involved in cell junctions and blastocyst formation and is essential for preimplantation embryo development (Kwon et al. 2016). A knockout mouse model illustrated that ADAM10 is also involved in embryonic cardiovascular development causing embryonic death after day 10.5 (Zhang C et al. 2010). Perhaps the role TSPAN15 plays in the formation of cell junctions and its higher expression in blastocysts with an increased capacity to implant into the endometrium is indicative of a greater likelihood of successful mammalian early embryo development (Eckert and Fleming 2008; Estill et al. 2019).
Novel ligands and modulators of triggering receptor expressed on myeloid cells receptor family: 2015-2020 updates
Published in Expert Opinion on Therapeutic Patents, 2021
Harbinder Singh, Vikrant Rai, Sunil K. Nooti, Devendra K. Agrawal
A Disintegrin and metalloproteinase domain-containing protein (ADAM10/17) is a cellular surface protein. These ADAMs cleave human TREM-2 at His157-Ser158 peptide bond and thus release sTREM-2. Further cleavage of transmembrane region of sTREM-2 by other enzymes (ℽ-secretase) release DAP12 and blocks sTREM-2 signaling. Inhibiting or initiating the shedding of TREM-2 is another approach of intervention [111]. However, due to the vast range of substrates of ADAM10/17, it is unable to inhibit specific protease or substrate activity because this may lead to various unwanted side effects. So, there is a pressing need for specific and fine-tuned modulation to block TREM-2 shedding. At the German center for neurodegenerative diseases, scientists targeted the cleavage site of TREM-2 to interrupt receptor shedding by ADAMs that increased the membrane concentration of receptor and amplify the signaling. They developed antibody 4D9 that could bind to the stalk region of TREM-2 and disrupt the proteolytic shedding [112]. Additionally, this antibody was also found to activate TREM-2 signaling and increase Aβ uptake thus cause microglia survival. Furthermore, in 2020, they also tested the antibody 4D9 in mouse model of AD and found that antibody significantly reduced the level of Aβ plaques but did not improve cognitive ability [113].
Further understanding of glioma mechanisms of pathogenesis: implications for therapeutic development
Published in Expert Review of Anticancer Therapy, 2020
Michael Ruff, Sani Kizilbash, Jan Buckner
A recently described mechanism of a direct neuronal activity to a glioma mitogen link implicates neuronal activity-dependent cleavage on a synaptic-adhesion molecule, neuroligin-3 (NLGN3), which binds to glioma cells similarly as it does for the native oligodendrocyte or oligodendrocyte progenitor cell and stimulates the PIK3-mTOR pathway [56]. NLGN3 sends the glioma cell a mitogenic signal that predominantly facilitates an oligodendrocyte progenitor-cell gene-expression profile pattern. Additionally, NLGN3 offers positive feedback, which results in glioma-cell surface expression of NLGN3, which can then be cleaved. NLGN3 is cleaved from neurons and oligodendrocyte-progenitor cells via ADAM10 sheddase, which can be inhibited by ADAM inhibitors such as INCB3619. ADAM10 sheddase inhibitors prevent the release of neuroligin-3 into the tumor microenvironment and block glioma growth in xenograft models [56]. The association of ADAM10 with glioblastoma-cell migration and invasion has previously been demonstrated. Notably, the up-regulation of ADAM10 sheddase has been demonstrated in more invasive glioblastoma cell lines and in human specimens [57]. The ADAM10-expression levels have correlated with tumor progression as well as the grade of malignancy. Inhibitors of the ADAM family of enzymes have been used in lymphoma and breast cancer [58]. There is very important a direct neuronal activity to glioma link. Clinical trials are to be underway in the very near future with agents targeting ADAM10 in human glioma. Currently, the ADAM10 inhibitor INCB7839 is currently being explored for use in glioma [56].