Part-time α-secretases: the functional biology of ADAM 9, 10 and 17
ABSTRACT Disintegrin metalloproteases of the ADAM family form a large (at present > 40 members in mammals) family of multidomain membrane proteins that in their ectodomain combine a cystein-rich, disintegrin and a zinc metalloprotease domain. Via their metalloprotease domain, ADAMs are often implicated in ectodomain shedding, either to release e.g. growth factors or to initiate further intracellular signalling via regulated intramembrane proteolysis. Mainly based upon overexpression studies in vehicle cells, three of them, ADAMs 9, 10 and 17, have been proposed to act as alpha-secretases for amyloid precursor protein (APP). It is striking thereby that this role has since then remained somewhat ill-defined, as APP processing in ADAM9 deficient neurons is unaltered, and also ADAM10 deficient murine embryonic fibroblasts exhibit at best a highly variable reduction in alpha-secretase activity. However, during the past years, numerous other substrates have been linked to all three sheddases, the cleavage of which in some cases appears to be strikingly more important for the organism than APP processing. Most notably, the perinatally lethal phenotype of ADAM17 knockout mice is dominated by a loss of growth factor shedding, while the even earlier fatal effects of ADAM10 deficiency exhibit key features of disabled Notch signalling and possibly also cadherin processing defects. In this review, we will summarize the published data on the "non-APP" functions of all three ADAMs, the further evaluation of which may be crucial when attempting to treat Alzheimer s Disease by increasing their expression and/or activity. As the knockouts of ADAM10 and ADAM17 are only informative for their roles in (early) development, while a number of recently assigned new substrates play crucial roles in the normal and/or diseased adult organism as well, work on conditional knockout models will be crucial to fully characterize both the full functional portfolio of (candidate) alpha-secretases as well as their clinical relevance, which may go way beyond Alzheimer s Disease.
- SourceAvailable from: Bryan Maloney
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- "Although APP-related research is generally in the context of AD pathogenesis, the non-amyloidogenic (non-Aβ) " alpha " route is actually the predominant pathway for APP processing (Postina, 2008). Its rate-limiting enzyme is the α-secretase family of " a disintegrin and metalloprotease " (ADAM) proteins (ADAM9, 10, and 17; Deuss et al., 2008; Vingtdeux and Marambaud, 2012). In addition to potential " anti-pruning " activity, ADAM17 induces cellular proliferation in a variety of conditions (Gooz et al., 2009; Lin et al., 2012). "
ABSTRACT: Autism is a neurodevelopmental disorder marked by social skills and communication deficits and interfering repetitive behavior. Intellectual disability often accompanies autism. In addition to behavioral deficits, autism is characterized by neuropathology and brain overgrowth. Increased intracranial volume often accompanies this brain growth. We have found that the Alzheimer's disease (AD) associated amyloid-β precursor protein (APP), especially its neuroprotective processing product, secreted APP α, is elevated in persons with autism. This has led to the "anabolic hypothesis" of autism etiology, in which neuronal overgrowth in the brain results in interneuronal misconnections that may underlie multiple autism symptoms. We review the contribution of research in brain volume and of APP to the anabolic hypothesis, and relate APP to other proteins and pathways that have already been directly associated with autism, such as fragile X mental retardation protein, Ras small GTPase/extracellular signal-regulated kinase, and phosphoinositide 3 kinase/protein kinase B/mammalian target of rapamycin. We also present additional evidence of magnetic resonance imaging intracranial measurements in favor of the anabolic hypothesis. Finally, since it appears that APP's involvement in autism is part of a multi-partner network, we extend this concept into the inherently interactive realm of epigenetics. We speculate that the underlying molecular abnormalities that influence APP's contribution to autism are epigenetic markers overlaid onto potentially vulnerable gene sequences due to environmental influence.Frontiers in Cellular Neuroscience 06/2013; 7:94. DOI:10.3389/fncel.2013.00094 · 4.18 Impact Factor
- ". Evidence that ADAM-9, ADAM-10 and ADAM-17 lack α-secretase activity under physiological conditions however, was the failure to find decreased APP processing in cells in which these genes had been deleted . Thus, the biological significance of these α-secretase activities in the processing of APP is still unclear. "
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- "Members of this family are membrane-anchored proteins that have been implicated in a variety of biological processes , including neurogenesis. The product of ADAM9 is believed to act as an α-secretase and cause non amyloidogenic cleavage of APP (Allinson et al. 2003; Cong and Jia 2011; Deuss et al. 2008). "
ABSTRACT: Animal studies suggest that early-life lead exposure influences gene expression and production of proteins associated with Alzheimer's disease (AD). We attempted to assess the relationship between early-life lead exposure and potential biomarkers for AD among young men and women. We also attempted to assess whether early-life lead exposure was associated with changes in expression of AD-related genes. We used sandwich enzyme-linked immunosorbent assays (ELISA) to measure plasma concentrations of amyloid β proteins Aβ40 and Aβ42 among 55 adults who had participated as newborns and young children in a prospective cohort study of the effects of lead exposure on development. We used RNA microarray techniques to analyze gene expression. Mean plasma Aβ42 concentrations were lower among 13 participants with high umbilical cord blood lead concentrations (≥ 10 μg/dL) than in 42 participants with lower cord blood lead concentrations (p = 0.08). Among 10 participants with high prenatal lead exposure, we found evidence of an inverse relationship between umbilical cord lead concentration and expression of ADAM metallopeptidase domain 9 (ADAM9), reticulon 4 (RTN4), and low-density lipoprotein receptor-related protein associated protein 1 (LRPAP1) genes, whose products are believed to affect Aβ production and deposition. Gene network analysis suggested enrichment in gene sets involved in nerve growth and general cell development. Data from our exploratory study suggest that prenatal lead exposure may influence Aβ-related biological pathways that have been implicated in AD onset. Gene network analysis identified further candidates to study the mechanisms of developmental lead neurotoxicity.Environmental Health Perspectives 02/2012; 120(5):702-7. DOI:10.1289/ehp.1104474 · 7.03 Impact Factor