Abeta-directed single-chain antibody delivery via a serotype-1 AAV vector improves learning behavior and pathology in Alzheimer's disease mice

Alzheimer's disease (AD) is a progressive dementing disorder characterized by age-related amyloid-beta (Abeta) deposition, neurofibrillary tangles, and synapse and neuronal loss. It is widely recognized that Abeta is a principal pathogenic mediator of AD. Our goal was to develop an immunotherap...

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Bibliographic Details
Published in:Molecular therapy 2010-08, Vol.18 (8), p.1471-1481
Main Authors: Ryan, Deborah A, Mastrangelo, Michael A, Narrow, Wade C, Sullivan, Mark A, Federoff, Howard J, Bowers, William J
Format: Article
Language:English
Subjects:
Alzheimer Disease - metabolism
Alzheimer Disease - pathology
Alzheimer Disease - therapy
Amyloid beta-Peptides - immunology
Animals
Cell Survival - genetics
Cell Survival - physiology
Cells, Cultured
Cricetinae
Dependovirus - genetics
Enzyme-Linked Immunosorbent Assay
Humans
Immunohistochemistry
Male
Maze Learning - physiology
Mice
Mice, Transgenic
Single-Chain Antibodies - genetics
Single-Chain Antibodies - metabolism
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Summary:Alzheimer's disease (AD) is a progressive dementing disorder characterized by age-related amyloid-beta (Abeta) deposition, neurofibrillary tangles, and synapse and neuronal loss. It is widely recognized that Abeta is a principal pathogenic mediator of AD. Our goal was to develop an immunotherapeutic approach, which would specifically lead to the clearance and/or neutralization of Abeta in the triple transgenic mouse model (3xTg-AD). These mice develop the amyloid and tangle pathologies and synaptic dysfunction reminiscent of human AD. Using a human single-chain variable fragment (scFv) antibody phage display library, a novel scFv antibody specific to Abeta was isolated, its activity characterized in vitro, and its open reading frame subsequently cloned into a recombinant adeno-associated virus (rAAV) vector. Three-month-old 3xTg-AD mice were intrahippocampally infused with serotype-1 rAAV vectors encoding Abeta-scFv or a control vector using convection-enhanced delivery (CED). Mice receiving rAAV1-Abeta-scFv harbored lower levels of insoluble Abeta and hyperphosphorylated tau, and exhibited improved cognitive function as measured by the Morris Water Maze (MWM) spatial memory task. These results underscore the potential of gene-based passive vaccination for AD, and provide further rationale for the development of Abeta-targeting strategies for this debilitating disease.
ISSN:1525-0024
DOI:10.1038/mt.2010.111