Atomic force microscopic imaging of seeded fibril formation and fibril branching by the Alzheimer's disease amyloid-β protein
被引:405
|
作者:
Harper, JD
论文数: 0引用数: 0
h-index: 0
机构:Harvard Univ, Dept Chem & Chem Biol, Cambridge, MA 02138 USA
Harper, JD
Lieber, CM
论文数: 0引用数: 0
h-index: 0
机构:Harvard Univ, Dept Chem & Chem Biol, Cambridge, MA 02138 USA
Lieber, CM
Lansbury, PT
论文数: 0引用数: 0
h-index: 0
机构:Harvard Univ, Dept Chem & Chem Biol, Cambridge, MA 02138 USA
Lansbury, PT
机构:
[1] Harvard Univ, Dept Chem & Chem Biol, Cambridge, MA 02138 USA
[2] MIT, Dept Chem, Cambridge, MA 02139 USA
[3] Brigham & Womens Hosp, Ctr Neurol Dis, Boston, MA 02115 USA
[4] Harvard Univ, Sch Med, Boston, MA 02115 USA
来源:
CHEMISTRY & BIOLOGY
|
1997年
/
4卷
/
12期
关键词:
Alzheimer's disease;
amyloid;
atomic force microscopy;
nucleation;
protofibril seeding;
D O I:
10.1016/S1074-5521(97)90303-3
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:
Background: Amyloid plaques composed of the fibrillar form of the amyloid-beta protein (A beta) are the defining neuropathological feature of Alzheimer's disease (AD). A detailed understanding of the time course of amyloid formation could define steps in disease progression and provide targets for therapeutic intervention. Amyloid fibrils, indistinguishable from those derived from an AD brain, can be produced in vitro using a seeded polymerization mechanism. In its simplest form, this mechanism involves a cooperative transition from monomeric A beta to the amyloid fibril without the buildup of intermediates. Recently, however, a transient species, the A beta amyloid protofibril, has been identified. Here, we report studies of A beta amyloid protofibril and its seeded transition into amyloid fibrils using atomic force microscopy. Results: Seeding of the protofibril-to-fibril transition was observed. Preformed fibrils, but not protofibrils, effectively seeded this transition. The assembly state of A beta influenced the rate of seeded growth, indicating that protofibrils are fibril assembly precursors, The handedness of the helical surface morphology of fibrils depended on the chirality of A beta, Finally, branched and partially wound fibrils were observed. Conclusions: The temporal evolution of morphologies suggests that the protofibril-to-fibril transition is nucleation-dependent and that protofibril winding is involved in that transition. Fibril unwinding and branching may be essential for the post-nucleation growth process. The protofibrillar assembly intermediate is a potential target for AD therapeutics aimed at inhibiting amyloid formation and AD diagnostics aimed at detecting presymptomatic disease.
机构:
Acad Sinica, Genom Res Ctr, 128 Acad Rd,Sec 2, Taipei 115, Taiwan
Natl Def Med Ctr, Grad Inst Life Sci, Taipei, TaiwanAcad Sinica, Genom Res Ctr, 128 Acad Rd,Sec 2, Taipei 115, Taiwan
Lee, Ming-Che
Liao, Yi-Hung
论文数: 0引用数: 0
h-index: 0
机构:
Acad Sinica, Genom Res Ctr, 128 Acad Rd,Sec 2, Taipei 115, TaiwanAcad Sinica, Genom Res Ctr, 128 Acad Rd,Sec 2, Taipei 115, Taiwan
机构:
Acad Sinica, Genom Res Ctr, 128 Acad Rd,Sec 2, Taipei 115, Taiwan
Natl Def Med Ctr, Grad Inst Life Sci, Taipei, TaiwanAcad Sinica, Genom Res Ctr, 128 Acad Rd,Sec 2, Taipei 115, Taiwan