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