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
American Academy of Family Physicians (AAFP)
(Martineau et al. D-serine signaling in the brain: friend and foe. TINS 2006; 29(8):481-491)
TNFα
Modified from:Townsend KP, Pratico D. Novel therapeutic opportunities for Alzheimer’s disease: focus on nonsteroidal anti-inflammatory drugs. FASEB 2005; 19: 1592-1601.
α-secretase β-secretase
γ-secretase
CTFα/β: C-terminal fragments α/β APP: Amyloid precursor proteinAβ: Amyloid beta
Aβ fibril
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.
BACE: β-site APP cleaving enzyme or β-secretaseTACE: TNFα-converting enzymeCTFα/β: C-terminal fragments APP: Amyloid precursor proteinAβ: Amyloid betaBMS: Bristol Myers-Squibb
APP sAPPαsAPPβBACE
α-secretase
CTFβ (C99)
Aβ
CTFα (C83)
γ-secretase γ-secretase
p3
TACE
BMS-561392 proTNFsTNFα
TACE and BACE do not compete for
and ‘see’ two separate pools of APP
BMS: Bristol Myers-SquibbTAPI-1: TNFα Protease Inhibitor-1APPwt: Amyloid Precursor Protein Wild-typeAPPswe: Amyloid Precursor Protein Swedish MutationsAPPα : soluble APPα
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
APP sAPPαsAPPβBACE
α-secretase
CTFβ (C99)
Aβ
CTFα (C83)
γ-secretase γ-secretase
p3
TACE
BMS-561392 proTNFsTNFα
BMS: Bristol Myers-SquibbTAPI-1: TNFα Protease Inhibitor-1Fl-APP: Full length amyloid precursor proteinsAPPα : soluble amyloid precursor protein αDMSO: Dimethyl sulfoxide
Primary cortical neurons from Tg2576 mice
Fl-APP: Full length amyloid precursor proteinsAPPα : soluble amyloid precursor protein αsAPPβ : soluble amyloid precursor protein βDMSO: Dimethyl sulfoxide
APP sAPPαsAPPβBACE
α-secretase
CTFβ (C99)
Aβ
CTFα (C83)
γ-secretaseγ-secretase
p3
TACE
BMS-561392 proTNFsTNFα
Merck BACE inhibitor III
1. TACE activator
2. APP retained in TGN
APP sAPPαsAPPβBACE
α-secretase
CTFβ (C99)
Aβ
CTFα (C83)
γ-secretaseγ-secretase
p3
TACE
BMS-561392 proTNFsTNFα
TGN: trans-Golgi networkBMS: Bristol Myers-Squibbfl-APP: Full length amyloid precursor proteinsAPPα : soluble amyloid precursor protein αsAPPβ : soluble amyloid precursor protein βDMSO: Dimethyl sulfoxide
BMS: Bristol Myers-SquibbTAPI-1: TNFα Protease Inhibitor-1fl-APP: Full length amyloid precursor proteinsAPPα : soluble amyloid precursor protein αDMSO: Dimethyl sulfoxide
BMS: Bristol Myers-SquibbTAPI-1: TNFα Protease Inhibitor-1fl-APP: Full length amyloid precursor proteinsAPPα : soluble amyloid precursor protein αDMSO: Dimethyl sulfoxide
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
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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