title: Sendai virus vector-mediated brain-derived neurotrophic factor expression ameliorates memory deficits and synaptic degeneration in a transgenic mouse model of Alzheimer's disease.
abstract: Growing evidence suggests that decreased brain-derived neurotrophic factor (BDNF) levels are associated with Alzheimer's disease (AD) pathogenesis. Therefore, BDNF gene therapy is considered to be a promising therapeutic strategy for treating AD. Sendai virus (SeV) is a type I parainfluenza virus that does not interact with host chromosomes because of its strict cytoplasmic life cycle. Although SeV is nonpathogenic in primates, including humans, its infectivity for neurons is strong. Here we demonstrate that SeV vectors effectively infected neurons, even though they were injected into subcortical white matter. Moreover, SeV vectors significantly induced BDNF expression, ameliorating synaptic degeneration and memory deficits in a transgenic mouse model of AD (Tg2576). This is the first study to demonstrate that viral vector administration in white matter is sufficient to restore cognitive function in vivo. These results also support the feasibility of using SeV vectors for gene therapy targeting the brain.
authors.affiliation: Laboratory of Disease Control, Tsukuba Primate Research Center, National Institute of Biomedical Innovation, Ibaraki, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Iwasaki
authors.forename: Takayuki
authors.initials: T
authors.lastname: Negishi
authors.forename: Makoto
authors.initials: M
authors.lastname: Inoue
authors.forename: Tomoko
authors.initials: T
authors.lastname: Tashiro
authors.forename: Takeshi
authors.initials: T
authors.lastname: Tabira
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Kimura
mesh_terms: D000544:Alzheimer Disease / Q000150:complications* / Q000235:genetics; D016229:Amyloid beta-Peptides / Q000494:pharmacology; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000096:biosynthesis / Q000494:pharmacology / Q000627:therapeutic use*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D004195:Disease Models, Animal; D006624:Hippocampus / Q000473:pathology; D006801:Humans; D008297:Male; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D008569:Memory Disorders / Q000209:etiology / Q000473:pathology / Q000628:therapy; D051379:Mice; D008822:Mice, Transgenic; D009410:Nerve Degeneration / Q000209:etiology / Q000473:pathology / Q000628:therapy; D009474:Neurons / Q000187:drug effects; D010446:Peptide Fragments / Q000494:pharmacology; D029082:Sendai virus / Q000235:genetics / Q000502:physiology*; D013569:Synapses / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D019208:Brain-Derived Neurotrophic Factor; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40)