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Ähnlich wie JC Fall 2009-Role of TNFalpha-Converting Enzyme (TACE) Inhibition on Amyloid β Production and APP Processing In Vitro and In Vivo
Ähnlich wie JC Fall 2009-Role of TNFalpha-Converting Enzyme (TACE) Inhibition on Amyloid β Production and APP Processing In Vitro and In Vivo (20)
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JC Fall 2009-Role of TNFalpha-Converting Enzyme (TACE) Inhibition on Amyloid β Production and APP Processing In Vitro and In Vivo
- 1. Minkyu L. Kim,1 Bin Zhang,1 Ian P. Mills,1 Marcos E. Milla,2 Kurt R. Brunden,1 and Virginia M.-Y. Lee1 The Journal of Neuroscience, November 12, 2008 • 28(46):12052–12061
- 2. American Academy of Family Physicians (AAFP)
- 3. TNFα (Martineau et al. D-serine signaling in the brain: friend and foe. TINS 2006; 29(8):481-491)
- 4. α-secretase β-secretase γ-secretase Aβ fibril CTFα/β: C-terminal fragments α/β APP: Amyloid precursor protein Aβ: Amyloid beta Modified from:Townsend KP, Pratico D. Novel therapeutic opportunities for Alzheimer’s disease: focus on nonsteroidal anti-inflammatory drugs. FASEB 2005; 19: 1592-1601.
- 5. Campbell IK, Roberts LJ, Wicks IP. Molecular targets in immune-mediated diseases: the case of tumour necrosis factor and rheumatoid arthritis. Immunology and Cell Biology, 2003; 81(5):354-66.
- 6. proTNF BMS-561392 sAPPβ BACE APP CTFβ (C99) γ-secretase Aβ TACE α-secretase sTNFα sAPPα CTFα (C83) γ-secretase p3 BACE: β-site APP cleaving enzyme or β-secretase TACE: TNFα-converting enzyme CTFα/β: C-terminal fragments APP: Amyloid precursor protein Aβ: Amyloid beta BMS: Bristol Myers-Squibb
- 7. TACE and BACE do not compete for and ‘see’ two separate pools of APP
- 8. BMS IC50 CHO-proTNFα----0.15 μM TAPI-1 IC50 CHO-proTNFα---- 0.90 μM BMS IC50 CHO-APPwt----4.47 μM BMS IC50 CHO-APPswe----0.23 μM TAPI-1 IC50---- 59.1 μM BMS: Bristol Myers-Squibb TAPI-1: TNFα Protease Inhibitor-1 APPwt: Amyloid Precursor Protein Wild-type APPswe: Amyloid Precursor Protein Swedish Mutation sAPPα : soluble APPα
- 10. Primary cortical neurons from Tg2576 mice BMS: Bristol Myers-Squibb TAPI-1: TNFα Protease Inhibitor-1 Fl-APP: Full length amyloid precursor protein sAPPα : soluble amyloid precursor protein α DMSO: Dimethyl sulfoxide
- 11. Merck BACE inhibitor III BMS-561392 proTNF sTNFα BACE sAPPβ APP CTFβ (C99) γ-secretase TACE α-secretase sAPPα CTFα (C83) γ-secretase Aβ p3 Fl-APP: Full length amyloid precursor protein sAPPα : soluble amyloid precursor protein α sAPPβ : soluble amyloid precursor protein β DMSO: Dimethyl sulfoxide
- 12. 1. TACE activator 2. APP retained in TGN
- 14. TGN: trans-Golgi network BMS: Bristol Myers-Squibb fl-APP: Full length amyloid precursor protein sAPPα : soluble amyloid precursor protein α sAPPβ : soluble amyloid precursor protein β DMSO: Dimethyl sulfoxide
- 15. BMS: Bristol Myers-Squibb TAPI-1: TNFα Protease Inhibitor-1 fl-APP: Full length amyloid precursor protein sAPPα : soluble amyloid precursor protein α DMSO: Dimethyl sulfoxide
- 16. BMS: Bristol Myers-Squibb TAPI-1: TNFα Protease Inhibitor-1 fl-APP: Full length amyloid precursor protein sAPPα : soluble amyloid precursor protein α DMSO: Dimethyl sulfoxide
- 17. BMS-561392 does not increase Aβ secretion under normal conditions Although TACE and BACE reside in a shared TGN compartment, TACE targeted anti-inflammatory drugs in AD may not be associated with higher Aβ generation BMS itself is an unlikely candidate for AD
- 18. Develop CNS penetrating TACE inhibitors Immunohistochemical analysis for effect of TACE inhibitors on β-amyloid Behavioral tests to check for benefit(s) of TACE inhibitors
Hinweis der Redaktion
- APP can be processed in different ways by different sets of enzymes - one pathway leads to amyloid plaque formation (amyloidogenic), while another does not (non-amyloidogenic). Usually about 90% of APP enters the non-amyloidogenic pathway, and 10% the amyloidogenic one, but these ratios can change due to mutations, environmental factors, as well as the age of the individual. Cleavage products from both these pathways may play important roles in neural development and function. Non-Plaque-forming (non-amyloidogenic) Pathway In the non-plaque-forming pathway, APP is cleaved first by a-secretase to yield a soluble N-terminal fragment (sAPPa) and a C-terminal fragment (CTFa). sAPPa may be involved in the enhancement of synaptogenesis, neurite outgrowth and neuronal survival, and are considered to be neuroprotective. CTFa is retained in the membrane, where it is acted upon by presenilin-containing g-secretase to yield a soluble N-terminal fragment (p3) and a membrane-bound C-terminal fragment (AICD, or APP intracellular domain). AICD may be involved in nuclear signalling via transcriptional regulation as well as axonal transport through its ability to associate with a host of different proteins. Plaque-forming (amyloidogenic) Pathway In the plaque-forming pathway, APP is cleaved first by a different enzyme, b-secretase (a transmembrane aspartic protease), yielding a soluble N-terminal fragment (sAPPb) and a membrane-bound C-terminal fragment (CTFb). This cut is made closer to the N-terminal end of APP than with a-secretase, making CTFb longer than CTFa. CTFb is then acted upon by g-secretase (as occurred in the previous pathway), yielding a membrane-bound C-terminal fragment (AICD) the same as before, and a soluble N-terminal fragment (amyloid-b, or Ab) that is longer than p3. Though Ab is required for neuronal function, it can accumulate in the extracellular space of the brain, where it can aggregate to form amyloid plaques. Ab can exert deleterious effects on neuronal and synaptic function, ultimately causing neuronal cell death. Plaque Formation Ab is ‘stickier’ than other APP fragments, and accumulates by stages into microscopic plaques. Plaques form by a multi-step polymerisation mechanism, with Ab peptides aggregating into oligomers, which cluster together to form fibrils with a regular b-sheet structure. These fibrils adhere together to form mats, which clump together with other substances to finally form plaques. Ab plaques may disrupt brain cells by clogging points of cell-cell communication, as well as activating immune cells that trigger inflammation, which can be lethal to cells. In addition, Ab is thought to cause oxidative damage to cells. Alzheimer’s Disease Ab is not all bad. Soluble Ab oligomers are required for Ab-induced inhibition of long-term-potentiation. However, the insoluble amyloid plaques appear to disrupt neuronal function. The problem may have to do with the aggregation state of the peptide, which in turn may be influenced by the concentration, structure and length of Ab peptide present. The concentration of Ab in the extracellular space may affect its toxicity by influencing its aggregation. Ab concentration appears to be influenced by several factors, including the level of neural activity and synaptic release, which seem to increase Ab levels. Age could also play a factor, studies showing that the level of a-secretase decreases with age, while b-secretase activity appears to increase. In addition, studies indicate that cholesterol may play a role in regulating Ab production, with high levels of cholesterol being linked with increased Ab release and plaque formation. One possible explanation for this result is the presence of cholesterol-rich regions of membranes known as lipid rafts, which may affect the distribution of APP-cleaving enzymes. The structure of the Ab oligomers could influence plaque formation. Whereas soluble monomeric Ab peptide has been shown to have an unordered structure in solution, within amyloid fibrils Ab adopts a regular b-sheet conformation. The conformational change to a b-sheet structure may trigger the formation of the abnormal fibrillar amyloid plaques found in AD patients. Ab peptides can differ in length from 38 to 42 amino acids. Ab ending at amino acid 42 (Ab42) appears to be the main species of Ab peptide deposited in plaques. In AD patients, studies show an increase in the ratio of Ab42 to Ab40. In addition, genetic changes involved in familial AD result in increased amounts of Ab42 present in the brain. Ab peptides are metal chelators with the ability to reduce those metals. For example, in vitro, Ab can reduce Cu2+ to Cu+, and Fe3+ to Fe2+. Ab42 appears to be a more effective reductant than Ab40, which may contribute to the ability of Ab42 to activate mononuclear phagocytes in the brain and elicit an inflammatory response. Therefore, it appears that there may be several contributory factors to plaque formation in AD patients, the relative importance of which still need to be deciphered.
- sAPPα was reduced by BMS in a dose dependent manner, sAPPβ level in the media remained unchanged CTFβ level remains unchanged
- BMS reduces the level of sAPPα in Tg2576 transgenic mouse primary neurons without changes in Aβ level