Gamma secretase-mediated notch signaling worsens brain damage and functional outcome in ischemic stroke

被引：235

作者：

Arumugam, TV

Chan, SL

Jo, DG

Yilmaz, G

Tang, SC

Cheng, AW

Gleichmann, M

Okun, E

Dixit, VD

Chigurupati, S

Mughal, MR

Ouyang, X

Miele, L

Magnus, T

Poosala, S

Granger, DN

Mattson, MP

机构：

[1] NIA, Neurosci Lab, Intramural Res Program, Baltimore, MD 21224 USA

[2] Louisiana State Univ, Hlth Sci Ctr, Dept Mol & Cellular Physiol, Shreveport, LA 71130 USA

[3] Natl Taiwan Univ Hosp, Dept Neurol, Stroke Ctr, Taipei, Taiwan

[4] NIA, Immunol Lab, Intramural Res Program, Baltimore, MD 21224 USA

[5] NIA, Res Resources Branch, Intramural Res Program, Baltimore, MD 21224 USA

[6] Univ Illinois, Dept Biopharmaceut Sci, Chicago, IL 60612 USA

[7] Univ Illinois, Ctr Canc, Chicago, IL 60612 USA

[8] Johns Hopkins Med Inst, Sch Med, Dept Neurosci, Baltimore, MD 21205 USA

来源：

NATURE MEDICINE | 2006年 / 12卷 / 06期

关键词：

D O I：

10.1038/nm1403

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Mice transgenic for antisense Notch and normal mice treated with inhibitors of the Notch-activating enzyme γ-secretase showed reduced damage to brain cells and improved functional outcome in a model of focal ischemic stroke. Notch endangers neurons by modulating pathways that increase their vulnerability to apoptosis, and by activating microglial cells and stimulating the infiltration of proinflammatory leukocytes. These findings suggest that Notch signaling may be a therapeutic target for treatment of stroke and related neurodegenerative conditions. © 2006 Nature Publishing Group.

引用

页码：621 / 623

页数：3

共 15 条

[1] Notch1 inhibits neurite outgrowth in postmitotic primary neurons [J].

Berezovska, O ;

McLean, P ;

Knowles, R ;

Frosh, M ;

Lu, FM ;

Lux, SE ;

Hyman, BT .

NEUROSCIENCE, 1999, 93 (02) :433-439

[2] Notch promotes survival of pre-T cells at the β-selection checkpoint by regulating cellular metabolism [J].

Ciofani, M ;

Zúñiga-Pflücker, JC .

NATURE IMMUNOLOGY, 2005, 6 (09) :881-888

[3] Notch to remember [J].

Costa, RM ;

Drew, C ;

Silva, AJ .

TRENDS IN NEUROSCIENCES, 2005, 28 (08) :429-435

[4] Functional gamma-secretase inhibitors reduce beta-amyloid peptide levels in brain [J].

Dovey, HF ;

John, V ;

Anderson, JP ;

Chen, LZ ;

Andrieu, PD ;

Fang, LY ;

Freedman, SB ;

Folmer, B ;

Goldbach, E ;

Holsztynska, EJ ;

Hu, KL ;

Johnson-Wood, KL ;

Kennedy, SL ;

Kholedenko, D ;

Knops, JE ;

Latimer, LH ;

Lee, M ;

Liao, Z ;

Lieberburg, IM ;

Motter, RN ;

Mutter, LC ;

Nietz, J ;

Quinn, KP ;

Sacchi, KL ;

Seubert, PA ;

Shopp, GM ;

Thorsett, ED ;

Tung, JS ;

Wu, J ;

Yang, S ;

Yin, CT ;

Schenk, DB ;

May, PC ;

Altstiel, LD ;

Bender, MH ;

Boggs, LN ;

Britton, TC ;

Clemens, JC ;

Czilli, DL ;

Dieckman-McGinty, DK ;

Droste, JJ ;

Fuson, KS ;

Gitter, BD ;

Hyslop, PA ;

Johnstone, EM ;

Li, WY ;

Little, SP ;

Mabry, TE ;

Miller, FD ;

Ni, B .

JOURNAL OF NEUROCHEMISTRY, 2001, 76 (01) :173-181

[5] Notch 1 signaling regulates peripheral T cell activation [J].

Eagar, TN ;

Tang, QZ ;

Wolfe, M ;

He, YP ;

Pear, WS ;

Bluestone, JA .

IMMUNITY, 2004, 20 (04) :407-415

[6] Inflammatory cell adhesion molecules in ischemic cerebrovascular disease [J].

Frijns, CJM ;

Kappelle, LJ .

STROKE, 2002, 33 (08) :2115-2122

[7] Notch-1 activation and dendritic atrophy in prion disease [J].

Ishikura, N ;

Clever, JL ;

Bouzamondo-Bernstein, E ;

Samayoa, E ;

Prusiner, SB ;

Huang, EJ ;

DeArmond, SJ .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2005, 102 (03) :886-891

[8] Apoptosis in neurodegenerative disorders [J].

Mattson, MP .

NATURE REVIEWS MOLECULAR CELL BIOLOGY, 2000, 1 (02) :120-129

[9] Modulation of notch processing by γ-secretase inhibitors causes intestinal goblet cell metaplasia and induction of genes known to specify gut secretory lineage differentiation [J].

Milano, J ;

McKay, J ;

Dagenais, C ;

Foster-Brown, L ;

Pognan, F ;

Gadient, R ;

Jacobs, RT ;

Zacco, A ;

Greenberg, B ;

Ciaccio, PJ .

TOXICOLOGICAL SCIENCES, 2004, 82 (01) :341-358

[10]

Pollack Scott J, 2005, Curr Opin Investig Drugs, V6, P35

← 1 2 →