Binding of beta-amyloid to the p75 neurotrophin receptor induces apoptosis - A possible mechanism for Alzheimer's disease

被引:290
作者
Yaar, M
Zhai, S
Pilch, PF
Doyle, SM
Eisenhauer, PB
Fine, RE
Gilchrest, BA
机构
[1] BOSTON UNIV, SCH MED, DEPT DERMATOL, BOSTON, MA 02118 USA
[2] BOSTON UNIV, SCH MED, DEPT BIOCHEM, BOSTON, MA 02118 USA
[3] VET AFFAIRS MED CTR, BEDFORD, MA 01730 USA
关键词
melanocytes; neurons; nerve growth factor; receptor binding; neurodegenerative;
D O I
10.1172/JCI119772
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
Alzheimer's disease is a neurodegenerative disorder characterized by the extracellular deposition in the brain of aggregated beta-amyloid peptide, presumed to play a pathogenic role, and by preferential loss of neurons that express the 75-kD neurotrophin receptor (p75(NTR)). Using rat cortical neurons and NIH-3T3 cell line engineered to stably express p75(NTR), we find that the beta-amyloid peptide specifically binds the p75(NTR). Furthermore, 3T3 cells expressing p75(NTR), but not wild-type control cells lacking the receptor, undergo apoptosis in the presence of aggregated beta-amyloid. Normal neural crest-derived melanocytes that express physiologic levels of p75(NTR) undergo apoptosis in the presence of aggregated beta-amyloid, but not in the presence of control peptide synthesized in reverse. These data imply that neuronal death in Alzheimer's disease is mediated, at least in part, by the interaction of beta-amyloid with p75(NTR), and suggest new targets for therapeutic intervention.
引用
收藏
页码:2333 / 2340
页数:8
相关论文
共 58 条
[1]   ZONE MAPPING OF THE BINDING DOMAIN OF THE RAT LOW-AFFINITY NERVE GROWTH-FACTOR RECEPTOR BY THE INTRODUCTION OF NOVEL N-GLYCOSYLATION SITES [J].
BALDWIN, AN ;
SHOOTER, EM .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1995, 270 (09) :4594-4602
[2]   MISSING ALZHEIMERS GENE FOUND [J].
BARINAGA, M .
SCIENCE, 1995, 269 (5226) :917-918
[3]  
BATTLEMAN DS, 1993, J NEUROSCI, V13, P941
[4]  
BAUER J, 1995, Z GERONTOL GERIATR, V28, P155
[5]   AMYLOID-BETA PEPTIDE INDUCES NECROSIS RATHER THAN APOPTOSIS [J].
BEHL, C ;
DAVIS, JB ;
KLIER, FG ;
SCHUBERT, D .
BRAIN RESEARCH, 1994, 645 (1-2) :253-264
[6]   HYDROGEN-PEROXIDE MEDIATES AMYLOID-BETA PROTEIN TOXICITY [J].
BEHL, C ;
DAVIS, JB ;
LESLEY, R ;
SCHUBERT, D .
CELL, 1994, 77 (06) :817-827
[7]   DIFFERENTIAL EXPRESSION OF NERVE GROWTH-FACTOR RECEPTORS LEADS TO ALTERED BINDING-AFFINITY AND NEUROTROPHIN RESPONSIVENESS [J].
BENEDETTI, M ;
LEVI, A ;
CHAO, MV .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1993, 90 (16) :7859-7863
[8]   The serpin-enzyme complex receptor recognizes soluble, nontoxic amyloid-beta peptide but not aggregated, cytotoxic amyloid-beta peptide [J].
Boland, K ;
Behrens, M ;
Choi, D ;
Manias, K ;
Perlmutter, DH .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1996, 271 (30) :18032-18044
[9]   A NOVEL PROTEIN THAT INTERACTS WITH THE DEATH DOMAIN OF FAS/APO1 CONTAINS A SEQUENCE MOTIF RELATED TO THE DEATH DOMAIN [J].
BOLDIN, MP ;
VARFOLOMEEV, EE ;
PANCER, Z ;
METT, IL ;
CAMONIS, JH ;
WALLACH, D .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1995, 270 (14) :7795-7798
[10]   Death of oligodendrocytes mediated by the interaction of nerve growth factor with its receptor p75 [J].
CasacciaBonnefil, P ;
Carter, BD ;
Dobrowsky, RT ;
Chao, MV .
NATURE, 1996, 383 (6602) :716-719