Intramuscular delivery of a single chain antibody gene reduces brain Abeta burden in a mouse model of Alzheimer's disease.
Anti-beta-amyloid (Abeta) immunotherapy has been well documented to effectively elicit amyloid plaque clearance and slow cognitive decline in experimental and clinical studies. However, anti-Abeta 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 Abeta could effectively inhibit the aggregation of Abeta and promote the disaggregation of preformed Abeta 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 Abeta level in the brain with a concomitant elevated Abeta 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 Abeta clearance and be promising in future drug development for the prevention and treatment of AD.
Department of Human Physiology and Centre for Neuroscience, Flinders University, SA, Australia.
Yan-Jiang
YJ
Wang
Anthony
A
Pollard
Jin-Hua
JH
Zhong
Xiao-Yan
XY
Dong
Xiao-Bing
XB
Wu
Hua-Dong
HD
Zhou
Xin-Fu
XF
Zhou
D000544:Alzheimer Disease / Q000235:genetics* / Q000473:pathology / Q000628:therapy*; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D004195:Disease Models, Animal; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods; D006801:Humans; D007273:Injections, Intramuscular; D051379:Mice; D008822:Mice, Transgenic; D057127:Single-Chain Antibodies / Q000008:administration & dosage* / Q000235:genetics*
D016229:Amyloid beta-Peptides; D057127:Single-Chain Antibodies