期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 105, 期 35, 页码 13145-13150出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0806192105
关键词
Alzheimer disease; protein import; human brain biopsies
资金
- Dainippon Sumitomo Pharma Company, Ltd.
- Gamla Tjanarinnor Foundation
- Gun och Bertil Stohnes Foundation
- The Foundation for Geriatric Diseases at Karolinska Institutet, Wallenbergs Foundation
- Swedish Research Council
- Swedish Foundation for Strategic Research
The amyloid beta-peptide (A beta) has been suggested to exert its toxicity intracellularly. Mitochondrial functions can be negatively affected by A beta and accumulation of All has been detected in mitochondria. Because A beta is not likely to be produced locally in mitochondria, we decided to investigate the mechanisms for mitochondrial A beta uptake. Our results from rat mitochondria show that A beta is transported into mitochondria via the translocase of the outer membrane (TOM) machinery. The import was insensitive to valinomycin, indicating that it is independent of the mitochondrial membrane potential. Subfractionation studies following the import experiments revealed A beta association with the inner membrane fraction, and immunoelectron microscopy after import showed localization of A beta to mitochondrial cristae. A similar distribution pattern of A beta in mitochondria was shown by immunoelectron microscopy in human cortical brain biopsies obtained from living subjects with normal pressure hydrocephalus. Thus, we present a unique import mechanism for A beta in mitochondria and demonstrate both in vitro and in vivo that A beta is located to the mitochondrial cristae. importantly, we also show that extracellulary applied A beta can be internalized by human neuroblastoma cells and can colocalize with mitochondrial markers. Together, these results provide further insight into the mitochondrial uptake of A beta, a peptide considered to be of major significance in Alzheimer's disease.
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