Bibliographic
This study investigated effects of adeno-associated viral vector mediated gene delivery of endothelin converting enzyme on Aβ levels in APPxPS1 Tg mice. The overall accumulation of Aβ in the brain is attributed to an imbalance between its production and degradation/clearance. In recent years several endogenous proteases have been found which degrade Aβ in the brain and other tissues both in vivo and in vitro. Several current studies have implicated ECE as an important enzyme in the degradation of Aβ and preventing its accumulation. ECE inhibitor, phosphoramidon, caused a rapid accumulation of Aβ in a cell line expressing ECE but not in cells lacking ECE expression. Subsequent studies revealed that overexpression of ECE in cell lines reduced Aβ accumulation by approximately 90%. In vivo data from ECE (+/−) transgenic mice, which show 25% reductions in ECE-1 activity, also show significant increases in both Aβ40 and Aβ42 levels in the brain. Moreover, intraventricular injections of phosphoramidon, increase Aß in wild type and APP transgenic mice. This study investigated the effects of upregulating the ECE-1 enzyme by using a rAAV vector, serotype 5, on Aβ load in the brain. Immunohistochemistry for the haemagglutinin tag appended to ECE revealed strong expression in areas surrounding the injection sites but minimal expression in the contralateral regions. Immunohistochemistry for Aß decreased in the anterior cortex and hippocampus of mice receiving ECE cDNA. Further, decreases in Congo red positive deposits were also observed in both regions. These results indicate that increasing the expression of β amyloid degrading enzymes through gene therapy is a promising therapeutic avenue through which to treat AD.