期刊
NEUROBIOLOGY OF AGING
卷 30, 期 3, 页码 364-376出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.neurobiolaging.2007.06.013
关键词
Alzheimer's disease; Amyloid-beta; Single chain antibody; Adeno-associated virus; Intramuscular delivery; Immunotherapy
资金
- Australian NHMRC [375109, 375110]
- FMC Foundation
- National 973 Fund of China [2004CB518806]
- Natural Science Foundation Project of CQ CSTC [200613135086]
- Chongqing Daping Hospital Foundation [HGQD003]
Anti-beta-amyloid (A beta) immunotherapy has been well documented to effectively elicit amyloid plaque clearance and slow cognitive decline in experimental and clinical studies. However, anti-A beta immunotherapy was associated with detrimental effects of brain inflammation and microhemorrhage, presumably induced by T-cell-mediated and/or Fc-mediated inflammatory responses. In the present study, a single chain antibody (scFv) against A beta could effectively inhibit the aggregation of AP and promote the disaggregation of preformed A beta fibrils. The recombined adeno-associated virus vectors carrying the scFv gene were produced to delivery the scFv gene. Hippocampus delivery of the scFv gene was effective in reducing the amyloid plaque in the hippocampus of an Alzheimer's disease (AD) mouse model. Further studies demonstrated that intramuscular delivery of the scFv gene was as effective as intracranial delivery in reducing the total A beta level in the brain with a concomitant elevated A beta level in serum. No enhanced microglial activation, discernable T lymphocyte infiltration, and increased microhemorrhage were found after intracranial and intramuscular delivery of the scFv gene. Our results suggest that intramuscular delivery of the scFv gene would be a novel peripheral noninflammatory immunological modality targeting A beta clearance and be promising in future drug development for the prevention and treatment of AD. Crown Copyright (C) 2007 Published by Elsevier Inc. All rights reserved.
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