期刊
JOURNAL OF NEUROSCIENCE
卷 36, 期 49, 页码 12425-12435出版社
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.2016-16.2016
关键词
AAV vector; Alzheimer's disease; anti-tau antibody; passive immunization; PHF-tau; tauopathy
资金
- Appel Alzheimer's Research Institute
- Alzheimer's Drug Discovery Foundation
Passive immunization with anti-tau monoclonal antibodies has been shown by several laboratories to reduce age-dependent tau pathology and neurodegeneration in mutant tau transgenic mice. These studies have used repeated high weekly doses of various tau antibodies administered systemically for several months and have reported reduced tau pathology of similar to 40-50% in various brain regions. Here we show that direct intrahippocampal administration of the adeno-associated virus (AAV)-vectored anti-phospho-tau antibody PHF1 to P301S tau transgenic mice results in high and durable antibody expression, primarily in neurons. Hippocampal antibody levels achieved after AAV delivery were similar to 50-fold more than those reported following repeated systemic administration. In contrast to systemic passive immunization, we observed markedly reduced (>= 80-90%) hippocampal insoluble pathological tau species and neurofibrillary tangles following a single dose of AAV-vectored PHF1 compared with mice treated with an AAV-IgG control vector. Moreover, the hippocampal atrophy observed in untreated P301S mice was fully rescued by treatment with the AAV-vectored PHF1 antibody. Vectored passive immunotherapy with an anti-tau monoclonal antibody may represent a viable therapeutic strategy for treating or preventing such tauopathies as frontotemporal dementia, progressive supranuclear palsy, or Alzheimer's disease.
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