Intramuscular delivery of a single chain antibody gene prevents brain Aβ deposition and cognitive impairment in a mouse model of Alzheimer's disease.
Anti-beta-amyloid (Aβ) immunotherapy is effective in removing brain Aβ, but has shown to be associated with detrimental effects. We have demonstrated that Adeno-associated virus (AAV)-mediated delivery of an anti-Aβ single chain antibody (scFv) gene was effective in clearing brain Aβ without eliciting any inflammatory side effects in old APP(Swe)/PS1dE9 transgenic mice. In the present study, we tested the efficacy and safety of intramuscular delivery of the scFv gene in preventing brain Aβ deposition. The scFv gene was intramuscularly delivered to APP(Swe)/PS1dE9 transgenic mice at 3 months of age, prior to Aβ deposition in the brain. Six months later, we found that the transgenes were expressed in a stable form at the delivered sites, with a small amount of ectopic expression in the liver and olfactory bulb. Brain Aβ plaque formation, Aβ accumulation, AD-type pathologies and cognitive impairment were significantly attenuated in scFv-treated APP(Swe)/PS1dE9 transgenic mice relative to EGFP-treated mice. Intramuscular delivery of scFv gene was well tolerated by the animals, did not cause inflammation or microhemorrhage at the gene expression site and in the brain, and did not induce neutralizing antibodies in the animals. These findings suggest that peripheral application of scFv is effective and safe in preventing the development of Alzheimer's disease (AD), and would be a promising non-inflammatory immunological modality for prevention and treatment of AD.
Wang
Yan-Jiang
YJ
Department of Human Physiology, Center for Neuroscience, Flinders University, Adelaide 5042, Australia. yanjiang_wang@tmmu.edu.cn
Gao
Chang-Yue
CY
Yang
Miao
M
Liu
Xiao-Hong
XH
Sun
Yin
Y
Pollard
Anthony
A
Dong
Xiao-Yan
XY
Wu
Xiao-Bing
XB
Zhong
Jin-Hua
JH
Zhou
Hua-Dong
HD
Zhou
Xin-Fu
XF
D023582:Alzheimer Vaccines / Q000627:therapeutic use*; D016229:Amyloid beta-Peptides / Q000097:blood / Q000276:immunology* / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D001923:Brain Chemistry / Q000187:drug effects*; D003072:Cognition Disorders / Q000276:immunology* / Q000517:prevention & control* / Q000523:psychology; D016207:Cytokines / Q000097:blood / Q000378:metabolism; D000229:Dependovirus / Q000235:genetics; D004797:Enzyme-Linked Immunosorbent Assay; D005822:Genetic Vectors; D006801:Humans; D007091:Image Processing, Computer-Assisted; D007273:Injections, Intramuscular; D051379:Mice; D008822:Mice, Transgenic; D053763:Presenilins / Q000235:genetics; D057127:Single-Chain Antibodies / Q000008:administration & dosage / Q000494:pharmacology*
D023582:Alzheimer Vaccines; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D016207:Cytokines; D053763:Presenilins; D057127:Single-Chain Antibodies