Dysregulated expression of miR-140 and miR-122 compromised microglial chemotaxis and led to reduced restriction of AD pathology.

BACKGROUND: Deposition of amyloid ß, which is produced by amyloidogenic cleavage of APP by ß- and γ-secretase, is one of the primary hallmarks of AD pathology. APP can also be processed by α- and γ-secretase sequentially, to generate sAPPα, which has been shown to be neuroprotective by promoting neurite outgrowth and neuronal survival, etc. METHODS: The global expression profiles of miRNA in blood plasma samples taken from 11 AD patients as well as from 14 age and sex matched cognitively normal volunteers were analyzed using miRNA-seq. Then, overexpressed miR-140 and miR-122 both in vivo and in vitro, and knock-down of the endogenous expression of miR-140 and miR-122 in vitro. Used a combination of techniques, including molecular biology, immunohistochemistry, to detect the impact of miRNAs on AD pathology. RESULTS: In this study, we identified that two miRNAs, miR-140-3p and miR-122-5p, both targeting ADAM10, the main α-secretase in CNS, were upregulated in the blood plasma of AD patients. Overexpression of these two miRNAs in mouse brains induced cognitive decline in wild type C57BL/6J mice as well as exacerbated dyscognition in APP/PS1 mice. Although significant changes in APP and total Aß were not detected, significantly downregulated ADAM10 and its non-amyloidogenic product, sAPPα, were observed in the mouse brains overexpressing miR-140/miR-122. Immunohistology analysis revealed increased neurite dystrophy that correlated with the reduced microglial chemotaxis in the hippocampi of these mice, independent of the other two ADAM10 substrates (neuronal CX3CL1 and microglial TREM2) that were involved in regulating the microglial immunoactivity. Further in vitro analysis demonstrated that both the reduced neuritic outgrowth of mouse embryonic neuronal cells overexpressing miR-140/miR-122 and the reduced Aß phagocytosis in microglia cells co-cultured with HT22 cells overexpressing miR-140/miR-122 could be rescued by overexpressing the specific inhibitory sequence of miR-140/miR-122 TuD as well as by addition of sAPPα, rendering these miRNAs as potential therapeutic targets. CONCLUSIONS: Our results suggested that neuroprotective sAPPα was a key player in the neuropathological progression induced by dysregulated expression of miR-140 and miR-122. Targeting these miRNAs might serve as a promising therapeutic strategy in AD treatment.

Cleavage site-directed antibodies reveal the prion protein in humans is shed by ADAM10 at Y226 and associates with misfolded protein deposits in neurodegenerative diseases.

Proteolytic cell surface release ('shedding') of the prion protein (PrP), a broadly expressed GPI-anchored glycoprotein, by the metalloprotease ADAM10 impacts on neurodegenerative and other diseases in animal and in vitro models. Recent studies employing the latter also suggest shed PrP (sPrP) to be a ligand in intercellular communication and critically involved in PrP-associated physiological tasks. Although expectedly an evolutionary conserved event, and while soluble forms of PrP are present in human tissues and body fluids, for the human body neither proteolytic PrP shedding and its cleavage site nor involvement of ADAM10 or the biological relevance of this process have been demonstrated thus far. In this study, cleavage site prediction and generation (plus detailed characterization) of sPrP-specific antibodies enabled us to identify PrP cleaved at tyrosin 226 as the physiological and apparently strictly ADAM10-dependent shed form in humans. Using cell lines, neural stem cells and brain organoids, we show that shedding of human PrP can be stimulated by PrP-binding ligands without targeting the protease, which may open novel therapeutic perspectives. Site-specific antibodies directed against human sPrP also detect the shed form in brains of cattle, sheep and deer, hence in all most relevant species naturally affected by fatal and transmissible prion diseases. In human and animal prion diseases, but also in patients with Alzheimer`s disease, sPrP relocalizes from a physiological diffuse tissue pattern to intimately associate with extracellular aggregated deposits of misfolded proteins characteristic for the respective pathological condition. Findings and research tools presented here will accelerate novel insight into the roles of PrP shedding (as a process) and sPrP (as a released factor) in neurodegeneration and beyond.

Endothelial cell sphingosine 1-phosphate receptor 1 restrains VE-cadherin cleavage and attenuates experimental inflammatory arthritis.

In rheumatoid arthritis, inflammatory mediators extravasate from blood into joints via gaps between endothelial cells (ECs), but the contribution of ECs is not known. Sphingosine 1-phosphate receptor 1 (S1PR1), widely expressed on ECs, maintains the vascular barrier. Here, we assessed the contribution of vascular integrity and EC S1PR1 signaling to joint damage in mice exposed to serum-induced arthritis (SIA). EC-specific deletion of S1PR1 or pharmacological blockade of S1PR1 promoted vascular leak and amplified SIA, whereas overexpression of EC S1PR1 or treatment with an S1PR1 agonist delayed SIA. Blockade of EC S1PR1 induced membrane metalloproteinase-dependent cleavage of vascular endothelial cadherin (VE-cadherin), a principal adhesion molecule that maintains EC junctional integrity. We identified a disintegrin and a metalloproteinase domain 10 (ADAM10) as the principal VE-cadherin "sheddase." Mice expressing a stabilized VE-cadherin construct had decreased extravascular VE-cadherin and vascular leakage in response to S1PR1 blockade, and they were protected from SIA. Importantly, patients with active rheumatoid arthritis had decreased circulating S1P and microvascular expression of S1PR1, suggesting a dysregulated S1P/S1PR1 axis favoring vascular permeability and vulnerability. We present a model in which EC S1PR1 signaling maintains homeostatic vascular barrier function by limiting VE-cadherin shedding mediated by ADAM10 and suggest this signaling axis as a therapeutic target in inflammatory arthritis.

Propolis Reduces Inflammation and Dyslipidemia Caused by High-Cholesterol Diet in Mice by Lowering ADAM10/17 Activities.

Atherosclerosis is one of the most important causes of cardiovascular diseases. A disintegrin and metalloprotease (ADAM)10 and ADAM17 have been identified as important regulators of inflammation in recent years. Our study investigated the effect of inhibiting these enzymes with selective inhibitor and propolis on atherosclerosis. In our study, C57BL/6J mice (n = 16) were used in the control and sham groups. In contrast, ApoE-/- mice (n = 48) were used in the case, water extract of propolis (WEP), ethanolic extract of propolis (EEP), GW280264X (GW-synthetic inhibitor), and solvent (DMSO and ethanol) groups. The control group was fed a control diet, and all other groups were fed a high-cholesterol diet for 16 weeks. WEP (400 mg/kg/day), EEP (200 mg/kg/day), and GW (100 µg/kg/day) were administered intraperitoneally for the last four weeks. Animals were sacrificed, and blood, liver, aortic arch, and aortic root tissues were collected. In serum, total cholesterol (TC), triglycerides (TGs), and glucose (Glu) were measured by enzymatic colorimetric method, while interleukin-1ß (IL-1ß), paraoxonase-1 (PON-1), and lipoprotein-associated phospholipase-A2 (Lp-PLA2) were measured by ELISA. Tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ), myeloperoxidase (MPO), interleukin-6 (IL-6), interleukin-10 (IL-10), and interleukin-12 (IL-12) levels were measured in aortic arch by ELISA and ADAM10/17 activities were measured fluorometrically. In addition, aortic root and liver tissues were examined histopathologically and immunohistochemically (ADAM10 and sortilin primary antibody). In the WEP, EEP, and GW groups compared to the case group, TC, TG, TNF-α, IL-1ß, IL-6, IL-12, PLA2, MPO, ADAM10/17 activities, plaque burden, lipid accumulation, ADAM10, and sortilin levels decreased, while IL-10 and PON-1 levels increased (p < 0.003). Our study results show that propolis can effectively reduce atherosclerosis-related inflammation and dyslipidemia through ADAM10/17 inhibition.

G protein-coupled estrogen receptor agonist G-1 decreases ADAM10 levels and NLRP3-inflammasome component activation in response to Staphylococcus aureus alpha-hemolysin.

The G protein-coupled estrogen receptor, also known as GPER1 or originally GPR30, is found in various tissues, indicating its diverse functions. It is typically present in immune cells, suggesting its role in regulating immune responses to infectious diseases. Our previous studies have shown that G-1, a selective GPER agonist, can limit the pathogenesis mediated by Staphylococcus aureus alpha-hemolysin (Hla). It aids in clearing bacteria in a mouse skin infection model and restricts the surface display of the Hla receptor, ADAM10 (a disintegrin and metalloprotease 10) in HaCaT keratinocytes. In this report, we delve into the modulation of GPER in human immune cells in relation to the NLRP3 inflammasome. We used macrophage-like differentiated THP-1 cells for our study. We found that treating these cells with G-1 reduces ATP release, decreases the activity of the caspase-1 enzyme, and lessens cell death following Hla intoxication. This is likely due to the reduced levels of ADAM10 and NLRP3 proteins, as well as the decreased display of the ADAM10 receptor in the G-1-treated THP-1 cells. Our studies, along with our previous work, suggest the potential therapeutic use of G-1 in reducing Hla susceptibility in humans. This highlights the importance of GPER in immune regulation and its potential as a therapeutic target.

Downregulation of the metalloproteinases ADAM10 or ADAM17 promotes osteoclast differentiation.

Bone resorption is driven through osteoclast differentiation by macrophage colony-stimulating factor (M-CSF) and receptor activator of nuclear factor kappa-Β ligand (RANKL). We noted that a disintegrin and metalloproteinase (ADAM) 10 and ADAM17 are downregulated at the expression level during osteoclast differentiation of the murine monocytic cell line RAW264.7 in response to RANKL. Both proteinases are well known to shed a variety of single-pass transmembrane molecules from the cell surface. We further showed that inhibitors of ADAM10 or ADAM17 promote osteoclastic differentiation and furthermore enhance the surface expression of receptors for RANKL and M-CSF on RAW264.7 cells. Using murine bone marrow-derived monocytic cells (BMDMCs), we demonstrated that a genetic deficiency of ADAM17 or its required regulator iRhom2 leads to increased osteoclast development in response to M-CSF and RANKL stimulation. Moreover, ADAM17-deficient osteoclast precursor cells express increased levels of the receptors for RANKL and M-CSF. Thus, ADAM17 negatively regulates osteoclast differentiation, most likely through shedding of these receptors. To assess the time-dependent contribution of ADAM10, we blocked this proteinase by adding a specific inhibitor on day 0 of BMDMC stimulation with M-CSF or on day 7 of subsequent stimulation with RANKL. Only ADAM10 inhibition beginning on day 7 increased the size of developing osteoclasts indicating that ADAM10 suppresses osteoclast differentiation at a later stage. Finally, we could confirm our findings in human peripheral blood mononuclear cells (PBMCs). Thus, downregulation of either ADAM10 or ADAM17 during osteoclast differentiation may represent a novel regulatory mechanism to enhance their differentiation process. Enhanced bone resorption is a critical issue in osteoporosis and is driven through osteoclast differentiation by specific osteogenic mediators. The present study demonstrated that the metalloproteinases ADAM17 and ADAM10 critically suppress osteoclast development. This was observed for a murine cell line, for isolated murine bone marrow cells and for human blood cells by either preferential inhibition of the proteinases or by gene knockout. As a possible mechanism, we studied the surface expression of critical receptors for osteogenic mediators on developing osteoclasts. Our findings revealed that the suppressive effects of ADAM17 and ADAM10 on osteoclastogenesis can be explained in part by the proteolytic cleavage of surface receptors by ADAM10 and ADAM17, which reduces the sensitivity of these cells to osteogenic mediators. We also observed that osteoclast differentiation was associated with the downregulation of ADAM10 and ADAM17, which reduced their suppressive effects. We therefore propose that this downregulation serves as a feedback loop for enhancing osteoclast development.

Alpha-secretase inhibition impairs Group I metabotropic glutamate receptor-mediated protein synthesis, long-term potentiation and long-term depression.

Group I metabotropic glutamate receptors (Gp1-mGluRs) exert a host of effects on cellular functions, including enhancement of protein synthesis and the associated facilitation of long-term potentiation (LTP) and induction of long-term depression (LTD). However, the complete cascades of events mediating these events are not fully understood. Gp1-mGluRs trigger α-secretase cleavage of amyloid precursor protein, producing soluble amyloid precursor protein-α (sAPPα), a known regulator of LTP. However, the α-cleavage of APP has not previously been linked to Gp1-mGluR's actions. Using rat hippocampal slices, we found that the α-secretase inhibitor tumour necrosis factor-alpha protease inhibitor-1, which inhibits both disintegrin and metalloprotease 10 (ADAM10) and 17 (ADAM17) activity, blocked or reduced the ability of the Gp1-mGluR agonist (R,S)-3,5-dihydroxyphenylglycine (DHPG) to stimulate protein synthesis, metaplastically prime future LTP and elicit sub-maximal LTD. In contrast, the specific ADAM10 antagonist GI254023X did not affect the regulation of plasticity, suggesting that ADAM17 but not ADAM10 is involved in mediating these effects of DHPG. However, neither drug affected LTD that was strongly induced by either high-concentration DHPG or paired-pulse synaptic stimulation. Our data suggest that moderate Gp1-mGluR activation triggers α-secretase sheddase activity targeting APP or other membrane-bound proteins as part of a more complex signalling cascade than previously envisioned. This article is part of a discussion meeting issue 'Long-term potentiation: 50 years on'.

Widespread genomic de novo DNA methylation occurs following CD8+ T cell activation and proliferation.

This research investigates the intricate dynamics of DNA methylation in the hours following CD8+ T cell activation, during a critical yet understudied temporal window. DNA methylation is an epigenetic modification central to regulation of gene expression and directing immune responses. Our investigation spanned 96-h post-activation and unveils a nuanced tapestry of global and site-specific methylation changes. We identified 15,626 significant differentially methylated CpGs spread across the genome, with the most significant changes occurring within the genes ADAM10, ICA1, and LAPTM5. While many changes had modest effect sizes, approximately 120 CpGs exhibited a log2FC above 1.5, with cell activation and proliferation pathways the most affected. Relatively few of the differentially methylated CpGs occurred along adjacent gene regions. The exceptions were seven differentially methylated gene regions, with the Human T cell Receptor Alpha Joining Genes demonstrating consistent methylation change over a 3kb window. We also investigated whether an inflammatory environment could alter DNA methylation during activation, with proliferating cells exposed to the oxidant glycine chloramine. No substantial differential methylation was observed in this context. The temporal perspective of early activation adds depth to the evolving field of epigenetic immunology, offering insights with implications for therapeutic innovation and expanding our understanding of epigenetic modulation in immune function.

ADAM10 as a major activator of reactive oxygen species production and klotho shedding in podocytes under diabetic conditions.

Early stages of diabetes are characterized by elevations of insulin and glucose concentrations. Both factors stimulate reactive oxygen species (ROS) production, leading to impairments in podocyte function and disruption of the glomerular filtration barrier. Podocytes were recently shown to be an important source of αKlotho (αKL) expression. Low blood Klotho concentrations are also associated with an increase in albuminuria, especially in patients with diabetes. We investigated whether ADAM10, which is known to cleave αKL, is activated in glomeruli and podocytes under diabetic conditions and the potential mechanisms by which ADAM10 mediates ROS production and disturbances of the glomerular filtration barrier. In cultured human podocytes, high glucose increased ADAM10 expression, shedding, and activity, NADPH oxidase activity, ROS production, and albumin permeability. These effects of glucose were inhibited when cells were pretreated with an ADAM10 inhibitor or transfected with short-hairpin ADAM10 (shADAM10) or after the addition soluble Klotho. We also observed increases in ADAM10 activity, NOX4 expression, NADPH oxidase activity, and ROS production in αKL-depleted podocytes. This was accompanied by an increase in albumin permeability in shKL-expressing podocytes. The protein expression and activity of ADAM10 also increased in isolated glomeruli and urine samples from diabetic rats. Altogether, these results reveal a new mechanism by which hyperglycemia in diabetes increases albumin permeability through ADAM10 activation and an increase in oxidative stress via NOX4 enzyme activation. Moreover, αKlotho downregulates ADAM10 activity and supports redox balance, consequently protecting the slit diaphragm of podocyteσ under hyperglycemic conditions.

Adipose tissue-selective ablation of ADAM10 results in divergent metabolic phenotypes following long-term dietary manipulation.

A Disintegrin And Metalloproteinase domain-containing protein 10 (ADAM10), is involved in several metabolic and inflammatory pathways. We speculated that ADAM10 plays a modulatory role in adipose tissue inflammation and metabolism. To this end, we studied adipose tissue-specific ADAM10 knock-out mice (aKO). While young, regular chow diet-fed aKO mice showed increased insulin sensitivity, following prolonged (33 weeks) high-fat diet (HFD) exposure, aKO mice developed obesity and insulin resistance. Compared to controls, aKO mice showed less inflammatory adipokine profile despite the significant increase in adiposity. In brown adipose tissue, aKO mice on HFD had changes in CD8+ T cell populations indicating a lesser inflammatory pattern. Following HFD, both aKO and control littermates demonstrated decreased adipose tissue pro-inflammatory macrophages, and increased anti-inflammatory accumulation, without differences between the genotypes. Collectively, our observations indicate that selective deletion of ADAM10 in adipocytes results in a mitigated inflammatory response, leading to increased insulin sensitivity in young mice fed with regular diet. This state of insulin sensitivity, following prolonged HFD, facilitates energy storage resulting in increased fat accumulation which ultimately leads to the development of a phenotype of obesity and insulin resistance. In conclusion, the data indicate that ADAM10 has a modulatory effect of inflammation and whole-body energy metabolism.

α5-nAChR/ADAM10 signaling mediates nicotine-related cutaneous melanoma progression via STAT3 activation.

Skin cutaneous melanoma (SKCM) is the skin malignancy with the highest mortality rate, and its morbidity rate is on the rise worldwide. Smoking is an independent marker of poor prognosis in melanoma. The α5-nicotinic acetylcholine receptor (α5-nAChR), one of the receptors for nicotine, is involved in the proliferation, migration and invasion of SKCM cells. Nicotine has been reported to promote the expression of a disintegrin and metalloproteinase 10 (ADAM10), which is the key gene involved in melanoma progression. Here, we explored the link between α5-nAChR and ADAM10 in nicotine-associated cutaneous melanoma. α5-nAChR expression was correlated with ADAM10 expression and lower survival in SKCM. α5-nAChR mediated nicotine-induced ADAM10 expression via STAT3. The α5-nAChR/ADAM10 signaling axis was involved in the stemness and migration of SKCM cells. Furthermore, α5-nAChR expression was associated with ADAM10 expression, EMT marker expression and stemness marker expression in nicotine-related mice homograft tissues. These results suggest the role of the α5-nAChR/ADAM10 signaling pathway in nicotine-induced melanoma progression.

Linarin Ameliorates Restenosis After Vascular Injury in Type 2 Diabetes Mellitus via Regulating ADAM10-Mediated Notch Signaling Pathway.

Vascular lesions frequently arise as complication in patients diagnosed with diabetes mellitus (DM). Presently, percutaneous coronary intervention (PCI) and antithrombotic therapy serve as primary treatments. However, in-stent restenosis persists as a challenging clinical issue following PCI, lacking sustained and effective treatment. Linarin (LN) exhibits diverse pharmacological activities and is regarded as a potential drug for treating various diseases, including DM. But its specific role in restenosis after vascular injury in DM patients remains unclear. A rat model of diabetes-related restenosis was established to evaluate the role of LN on neointimal hyperplasia. Vascular smooth muscle cells (VSMCs) stimulated by high glucose (HG, 30 mM) underwent LN treatment. Additionally, an overexpression plasmid of A disintegrin and metalloproteinases (ADAM10) was constructed to transfect VSMCs. We employed CCK-8, Brdu, wound-healing scratch, and transwell migration assays to evaluate the proliferation and migration of VSMCs. Furthermore, western blot and immunofluorescence assays were utilized to investigate the expressions of ADAM10 and the downstream Notch signaling pathway in vivo and in vitro models. LN notably alleviated intimal hyperplasia after vascular injury in DM rats and reduced the protein expression of ADAM10, alongside its downstream Notch1 signaling pathway-related proteins (Notch1, NICD and Hes1) in rat carotid artery tissues. LN effectively suppressed the proliferation and migration of VSMCs induced by HG, downregulating the protein expression of ADAM10, Notch1, NICD and Hes1. Moreover, our findings indicated that ADAM10 overexpression significantly reversed LN's effects on proliferation, migration, and the expression of Notch1 signaling pathway-related proteins in HG-treated VSMCs. LN demonstrates potential therapeutic efficacy in addressing restenosis after diabetic-related vascular injury, with the ADAM10 mediated Notch signaling pathway playing a pivotal role.

GW501516-Mediated Targeting of Tetraspanin 15 Regulates ADAM10-Dependent N-Cadherin Cleavage in Invasive Bladder Cancer Cells.

Bladder cancer aggressiveness is correlated with abnormal N-cadherin transmembrane glycoprotein expression. This protein is cleaved by the metalloprotease ADAM10 and the γ-secretase complex releasing a pro-angiogenic N-terminal fragment (NTF) and a proliferation-activating soluble C-terminal fragment (CTF2). Tetraspanin 15 (Tspan15) is identified as an ADAM10-interacting protein to induce selective N-cadherin cleavage. We first demonstrated, in invasive T24 bladder cancer cells, that N-cadherin was cleaved by ADAM10 generating NTF in the extracellular environment and leaving a membrane-anchored CTF1 fragment and that Tspan15 is required for ADAM10 to induce the selective N-cadherin cleavage. Targeting N-cadherin function in cancer is relevant to preventing tumor progression and metastases. For antitumor molecules to inhibit N-cadherin function, they should be complete and not cleaved. We first showed that the GW501516, an agonist of the nuclear receptor PPARß/δ, decreased Tspan15 and prevented N-cadherin cleavage thus decreasing NTF. Interestingly, the drug did not modify ADAM10 expression, which was important because it could limit side effects since ADAM10 cleaves numerous substrates. By targeting Tspan15 to block ADAM10 activity on N-cadherin, GW501516 could prevent NTF pro-tumoral effects and be a promising molecule to treat bladder cancer. More interestingly, it could optimize the effects of the N-cadherin antagonists those such as ADH-1 that target the N-cadherin ectodomain.

Plasma ADAM10 Levels and Their Association with Alzheimer's Disease Diagnosis in Older Adults with Fewer Years of Formal Education.

INTRODUCTION: Low educational attainment is a potential risk factor for Alzheimer's disease (AD) development. Alpha-secretase ADAM10 plays a central role in AD pathology, attenuating the formation of beta-amyloid peptides and, therefore, their aggregation into senile plaques. This study seeks to investigate ADAM10 as a blood-based biomarker in mild cognitive impairment (MCI) and AD in a diverse group of community-dwelling older adults, focusing on those with limited educational attainment. METHODS: Participants were recruited from public health services. Cognition was evaluated using Mini-Mental State Examination (MMSE) and Addenbrooke's Cognitive Examination - Revised (ACE-R) batteries. Blood samples were collected to analyze plasma ADAM10 levels. A logistic regression was conducted to verify the influence of plasma ADAM10 on the AD diagnosis. RESULTS: Significant differences in age, years of education, prescribed medications, and cognitive test scores were found between the MCI and AD groups. Regarding cognitive performance, both ACE-R and MMSE scores displayed significant differences between groups, with post hoc analyses highlighting these distinctions, particularly between AD and cognitively unimpaired individuals. Elevated plasma ADAM10 levels were associated with a 4.5-fold increase in the likelihood of a diagnosis of MCI and a 5.9-fold increase in the likelihood of a diagnosis of AD. These findings suggest ADAM10 levels in plasma as a valuable biomarker for assessing cognitive status in older individuals with low education attainment. CONCLUSION: This study underscores the potential utility of plasma ADAM10 levels as a blood-based biomarker for cognitive status, especially in individuals with low educational backgrounds, shedding light on their relevance in AD development and diagnosis.

A Disintegrin and metalloproteinase carves T cell abnormalities and pathogenesis in systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a complex autoimmune disorder impacting various organs, notably prevalent in women of reproductive age. This review explores the involvement of a disintegrin and metalloproteinases (ADAMs) in SLE pathogenesis. Despite advancements in understanding SLE through genome and transcriptome studies, the role of ADAMs in post-translational regulations remains insufficiently explored. ADAMs, transmembrane proteins with diverse functions, impact cell adhesion, migration, and inflammation by shedding cell surface proteins, growth factors, and receptors. Notably, ADAM9 is implicated in Th17 cell differentiation, which is crucial in SLE pathology. ADAM10 and ADAM17 play pivotal roles in T-cell biology, influencing immune cell development and differentiation. Elevated soluble ADAM substrates in SLE patients serve as potential biomarkers correlating with disease activity. Targeting ADAMs or their substrates offers promising therapeutic avenues for SLE management and treatment enhancement.

A Disintegrin And Metalloprotease 10 expression within the murine central nervous system.

A Disintegrin And Metalloprotease 10 (ADAM10), is able to control several important physiopathological processes through the shedding of a large number of protein substrates. Although ADAM10 plays a crucial role in the central nervous system (CNS) development and function, its protein distribution in the CNS has not been fully addressed. Here, we described the regional and cellular ADAM10 protein expression in C57BL/6 mice examined by immunofluorescence 1) throughout the adult mouse brain, cerebellum and spinal cord in vivo and 2) in different cell types as neurons, astrocytes, oligodendrocytes and microglia in vitro. We observed ADAM10 expression through the whole CNS, with a strong expression in the hippocampus, in the hypothalamus and in the cerebral and piriform cortex in the brain, in the Purkinje and in granular cell layers in the cerebellum and in the spinal cord to a lower extent. In vivo, ADAM10 protein expression was mainly found in neurons and in some oligodendroglial cell populations. However, in primary cultures we observed ADAM10 expression in neurons, oligodendrocytes, astrocytes and microglia. Interestingly, ADAM10 was not only found in the membrane but also in cytoplasmic vesicles and in the nucleus of primary cultured cells. Overall, this work highlights a wide distribution of ADAM10 throughout the CNS. The nuclear localization of ADAM10, probably due to its intracellular domain, emphasizes its role in cell signalling in physiological and pathological conditions. Further investigations are required to better elucidate the role of ADAM10 in glial cells.

Unraveling the dual role of ADAM10: Bridging the gap between cancer and Alzheimer's disease.

An inverse association between Alzheimer's disease (AD) and cancer has been proposed. Patients with a cancer history have a decreased risk of developing AD, and AD patients have a reduced cancer incidence, which is not seen in vascular dementia patients. Given this association, common molecular and biological mechanisms that could explain this inverse relationship have been proposed before, such as Peptidylprolyl Cis/Trans Isomerase, NIMA-Interacting 1 (Pin1), Wingless and Int-1 (Wnt), and transformation-related protein 53 (p53)-mediated pathways, along with inflammation and oxidative stress-related proteins. A Disintegrin And Metalloprotease 10 (ADAM10) is a protease responsible for the cleavage of key AD- and cancer-related substrates, and it has inverse roles in those diseases: neuroprotective and disease-promoting, respectively. Thus, herein, we review the relevant literature linking AD and cancer and propose how ADAM10 activity might modulate the inverse association between the diseases. Understanding how this protease mediates those two conditions might raise some considerations in the ADAM10 pharmacological modulation for treating AD and cancer.

Alternative mechanisms of Notch activation by partitioning into distinct endosomal domains.

Different membrane microdomain compositions provide unique environments that can regulate signaling receptor function. We identify microdomains on the endosome membrane of Drosophila endosomes, enriched in lipid-raft or clathrin/ESCRT-0, which are associated with Notch activation by distinct, ligand-independent mechanisms. Transfer of Notch between microdomains is regulated by Deltex and Suppressor of deltex ubiquitin ligases and is limited by a gate-keeper role for ESCRT complexes. Ubiquitination of Notch by Deltex recruits it to the clathrin/ESCRT-0 microdomain and enhances Notch activation by an ADAM10-independent/TRPML-dependent mechanism. This requirement for Deltex is bypassed by the downregulation of ESCRT-III. In contrast, while ESCRT-I depletion also activates Notch, it does so by an ADAM10-dependent/TRPML-independent mechanism and Notch is retained in the lipid raft-like microdomain. In the absence of such endosomal perturbation, different activating Notch mutations also localize to different microdomains and are activated by different mechanisms. Our findings demonstrate the interplay between Notch regulators, endosomal trafficking components, and Notch genetics, which defines membrane locations and activation mechanisms.

Direct interaction of platelet with tumor cell aggravates hepatocellular carcinoma metastasis by activating TLR4/ADAM10/CX3CL1 axis.

Metastasis is the main culprit of cancer-related death and account for the poor prognosis of hepatocellular carcinoma. Although platelets have been shown to accelerate tumor cell metastasis, the exact mechanism remained to be fully understood. Here, we found that high blood platelet counts and increased tumor tissue ADAM10 expression indicated the poor prognosis of HCC patients. Meanwhile, blood platelet count has positive correlation with tumor tissue ADAM10 expression. In vitro, we revealed that platelet increased ADAM10 expression in tumor cell through TLR4/NF-κB signaling pathway. ADAM10 catalyzed the shedding of CX3CL1 which bound to CX3CR1 receptor, followed by inducing epithelial to mesenchymal transition and activating RhoA signaling in cancer cells. Moreover, knockdown HCC cell TLR4 (Tlr4) or inhibition of ADAM10 prevented platelet-increased tumor cell migration, invasion and endothelial permeability. In vivo, we further verified in mice lung metastatic model that platelet accelerated tumor metastasis via cancer cell TLR4/ADAM10/CX3CL1 axis. Overall, our study provides new insights into the underlying mechanism of platelet-induced HCC metastasis. Therefore, targeting the TLR4/ADAM10/CX3CL1 axis in cancer cells hold promise for the inhibition of platelet-promoted lung metastasis of HCC.

Apoptosis-mediated ADAM10 activation removes a mucin barrier promoting T cell efferocytosis.

Efferocytic clearance of apoptotic cells in general, and T cells in particular, is required for tissue and immune homeostasis. Transmembrane mucins are extended glycoproteins highly expressed in the cell glycocalyx that function as a barrier to phagocytosis. Whether and how mucins may be regulated during cell death to facilitate efferocytic corpse clearance is not well understood. Here we show that normal and transformed human T cells express a subset of mucins which are rapidly and selectively removed from the cell surface during apoptosis. This process is mediated by the ADAM10 sheddase, the activity of which is associated with XKR8-catalyzed flipping of phosphatidylserine to the outer leaflet of the plasma membrane. Mucin clearance enhances uptake of apoptotic T cells by macrophages, confirming mucins as an enzymatically-modulatable barrier to efferocytosis. Together these findings demonstrate a glycocalyx regulatory pathway with implications for therapeutic intervention in the clearance of normal and transformed apoptotic T cells.