Herpes simplex virus RNAi and neprilysin gene transfer vectors reduce accumulation of Alzheimer's disease-related amyloid-β peptide in vivo

被引:83
作者
Hong, C-S
Goins, W. F.
Goss, J. R.
Burton, E. A.
Glorioso, J. C.
机构
[1] Univ Pittsburgh, Sch Med, Dept Mol Genet & Biochem, Pittsburgh, PA 15261 USA
[2] Univ Pittsburgh, Sch Med, Dept Neurol, Pittsburgh, PA 15261 USA
关键词
herpes simplex virus; Alzheimer's disease; amyloid-beta protein; siRNA; neprilysin; lentivirus;
D O I
10.1038/sj.gt.3302719
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Accumulation of insoluble aggregates of amyloid-beta peptide ( A beta), a cleavage product of amyloid precursor protein ( APP), is thought to be central to the pathogenesis of Alzheimer's disease ( AD). Consequently, downregulation of APP, or enhanced clearance of A beta, represent possible therapeutic strategies for AD. We generated replication-defective herpes simplex virus ( HSV) vectors that inhibit A beta accumulation, both in vitro and in vivo. In cell culture, HSV vectors expressing either ( i) short hairpin RNA directed to the APP transcript ( HSV-APP/shRNA), or ( ii) neprilysin, an endopeptidase that degrades A beta ( HSV-neprilysin), substantially inhibited accumulation of A beta. To determine whether these vectors showed similar activity in vivo, we developed a novel mouse model, in which overexpression of a mutant form of APP in the hippocampus, using a lentiviral vector ( LV-APP(Sw)), resulted in rapid A beta accumulation. Co-inoculation of LV-APP(Sw) with each of the HSV vectors showed that either HSV-APP/shRNA or HSV-neprilysin inhibited A beta accumulation in this model, whereas an HSV control vector did not. These studies demonstrate the utility of HSV vectors for reducing A beta accumulation in the brain, thus providing useful tools to clarify the role of A beta in AD that may facilitate the development of novel therapies for this important disease.
引用
收藏
页码:1068 / 1079
页数:12
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