摘要
Alzheimer's disease (AD) is a progressive dementing disorder characterized by age-related amyloid-beta (A beta) deposition, neurofibrillary tangles, and synapse and neuronal loss. It is widely recognized that A beta 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 A beta 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 A beta 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 A beta-scFv or a control vector using convection-enhanced delivery (CED). Mice receiving rAAV1-A beta-scFv harbored lower levels of insoluble A beta 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 A beta-targeting strategies for this debilitating disease.
- 出版日期2010-8