title: Vectored Intracerebral Immunization with the Anti-Tau Monoclonal Antibody PHF1 Markedly Reduces Tau Pathology in Mutant Tau Transgenic Mice.
abstract: 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 ∼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 ∼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.
  
  
  
  We have used an adeno-associated viral (AAV) vector to deliver the genes encoding an anti-phospho-tau monoclonal antibody, PHF1, directly to the brain of mice that develop neurodegeneration due to a tau mutation that causes frontotemporal dementia (FTD). When administered systemically, PHF1 has been shown to modestly reduce tau pathology and neurodegeneration. Since such antibodies do not readily cross the blood-brain barrier, we used an AAV vector to deliver antibody directly to the hippocampus and observed much higher antibody levels and a much greater reduction in tau pathology. Using AAV vectors to deliver antibodies like PHF1 directly to brain may constitute a novel approach to treating various neurodegenerative disorders, such as FTD and Alzheimer's disease.
authors.affiliation: Appel Alzheimer's Disease Research Institute, Feil Family Brain and Mind Research Institute, and.
authors.forename: Wencheng
authors.identifier: 0000-0002-4830-3209
authors.initials: W
authors.lastname: Liu
authors.affiliation: Appel Alzheimer's Disease Research Institute, Feil Family Brain and Mind Research Institute, and.
authors.forename: Lingzhi
authors.identifier: 0000-0002-4164-7279
authors.initials: L
authors.lastname: Zhao
authors.affiliation: Appel Alzheimer's Disease Research Institute, Feil Family Brain and Mind Research Institute, and.
authors.forename: Brittany
authors.initials: B
authors.lastname: Blackman
authors.affiliation: Appel Alzheimer's Disease Research Institute, Feil Family Brain and Mind Research Institute, and.
authors.forename: Mayur
authors.identifier: 0000-0003-4970-9857
authors.initials: M
authors.lastname: Parmar
authors.affiliation: Appel Alzheimer's Disease Research Institute, Feil Family Brain and Mind Research Institute, and.
authors.forename: Man Ying
authors.identifier: 0000-0002-2165-9328
authors.initials: MY
authors.lastname: Wong
authors.affiliation: Appel Alzheimer's Disease Research Institute, Feil Family Brain and Mind Research Institute, and.
authors.forename: Thomas
authors.identifier: 0000-0002-4742-1342
authors.initials: T
authors.lastname: Woo
authors.affiliation: Appel Alzheimer's Disease Research Institute, Feil Family Brain and Mind Research Institute, and.
authors.forename: Fangmin
authors.initials: F
authors.lastname: Yu
authors.affiliation: Department of Genetic Medicine, Weill Cornell Medicine, New York, New York 10021.
authors.forename: Maria J
authors.initials: MJ
authors.lastname: Chiuchiolo
authors.affiliation: Department of Genetic Medicine, Weill Cornell Medicine, New York, New York 10021.
authors.forename: Dolan
authors.initials: D
authors.lastname: Sondhi
authors.affiliation: Department of Genetic Medicine, Weill Cornell Medicine, New York, New York 10021.
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Kaminsky
authors.affiliation: Department of Genetic Medicine, Weill Cornell Medicine, New York, New York 10021.
authors.forename: Ronald G
authors.initials: RG
authors.lastname: Crystal
authors.affiliation: Appel Alzheimer's Disease Research Institute, Feil Family Brain and Mind Research Institute, and Steve@vygr.com.
authors.forename: Steven M
authors.identifier: 0000-0002-8388-2023
authors.initials: SM
authors.lastname: Paul
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000276:immunology*; D004268:DNA-Binding Proteins; D000229:Dependovirus / Q000276:immunology; D005260:Female; D006624:Hippocampus; D006801:Humans; D007116:Immunization, Passive / Q000379:methods*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008845:Microinjections; D009154:Mutation / Q000235:genetics; D016874:Neurofibrillary Tangles / Q000473:pathology; D063146:Polycomb-Group Proteins; D024801:Tauopathies / Q000276:immunology* / Q000517:prevention & control*; D014018:Tissue Distribution; D014157:Transcription Factors / Q000276:immunology*; D016875:tau Proteins / Q000235:genetics*
chemical_list: D000911:Antibodies, Monoclonal; D004268:DNA-Binding Proteins; C533390:Phf1 protein, mouse; D063146:Polycomb-Group Proteins; D014157:Transcription Factors; D016875:tau Proteins
keywords: AAV vector; Alzheimer's disease; PHF-tau; anti-tau antibody; passive immunization; tauopathy