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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 Neur...
American Academy of Family Physicians (AAFP)
TNFα

(Martineau et al. D-serine signaling in the brain: friend and foe. TINS 2006; 29(8):481-491)
α-secretase

β-secretase

γ-secretase

Aβ fibril
CTFα/β: C-terminal fragments α/β
APP: Amyloid precursor protein
Aβ: Amylo...
Campbell IK, Roberts LJ, Wicks IP. Molecular targets in immune-mediated diseases: the case of tumour necrosis factor
and r...
proTNF

BMS-561392
sAPPβ

BACE

APP

CTFβ (C99)
γ-secretase

Aβ

TACE
α-secretase

sTNFα

sAPPα

CTFα (C83)
γ-secretase

p...
TACE and BACE do not compete for
and ‘see’ two separate pools of APP
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----...
BMS-561392

proTNF
sTNFα

BACE
sAPPβ

APP

CTFβ (C99)
γ-secretase
Aβ

TACE
α-secretase

sAPPα

CTFα (C83)
γ-secretase
p3
Primary cortical neurons from
Tg2576 mice

BMS: Bristol Myers-Squibb
TAPI-1: TNFα Protease Inhibitor-1
Fl-APP: Full length...
Merck BACE
inhibitor III

BMS-561392

proTNF
sTNFα

BACE
sAPPβ

APP

CTFβ (C99)
γ-secretase

TACE
α-secretase

sAPPα

CTFα...
1.

TACE activator

2.

APP retained in TGN
BMS-561392

proTNF
sTNFα

BACE
sAPPβ

APP

CTFβ (C99)
γ-secretase

TACE
α-secretase

sAPPα

CTFα (C83)
γ-secretase

Aβ

p3
TGN: trans-Golgi network
BMS: Bristol Myers-Squibb
fl-APP: Full length amyloid precursor protein
sAPPα : soluble amyloid p...
BMS: Bristol Myers-Squibb
TAPI-1: TNFα Protease Inhibitor-1
fl-APP: Full length amyloid precursor protein
sAPPα : soluble ...
BMS: Bristol Myers-Squibb
TAPI-1: TNFα Protease Inhibitor-1
fl-APP: Full length amyloid precursor protein
sAPPα : soluble ...


BMS-561392 does not increase Aβ
secretion under normal conditions



Although TACE and BACE reside in a
shared TGN com...


Develop CNS penetrating TACE inhibitors



Immunohistochemical analysis for effect
of TACE inhibitors on β-amyloid


...
JC Fall 2009-Role of TNFalpha-Converting Enzyme (TACE) Inhibition on Amyloid β Production and APP Processing In Vitro and ...
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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

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JC 2009-Nisha Rizvi, SIU-SOM

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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. 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. 2. American Academy of Family Physicians (AAFP)
  3. 3. TNFα (Martineau et al. D-serine signaling in the brain: friend and foe. TINS 2006; 29(8):481-491)
  4. 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. 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. 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. 7. TACE and BACE do not compete for and ‘see’ two separate pools of APP
  8. 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
  9. 9. BMS-561392 proTNF sTNFα BACE sAPPβ APP CTFβ (C99) γ-secretase Aβ TACE α-secretase sAPPα CTFα (C83) γ-secretase p3
  10. 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. 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. 12. 1. TACE activator 2. APP retained in TGN
  13. 13. BMS-561392 proTNF sTNFα BACE sAPPβ APP CTFβ (C99) γ-secretase TACE α-secretase sAPPα CTFα (C83) γ-secretase Aβ p3
  14. 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. 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. 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. 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. 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

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