Reducing amyloid plaque burden via ex vivo gene delivery of an aβ-degrading protease:: A novel therapeutic approach to Alzheimer!Disease

Background Understanding the mechanisms of amyloid-beta protein ( A beta) production and clearance in the brain has been essential to elucidating the etiology of Alzheimer disease ( AD). Chronically decreasing brain A beta levels is an emerging therapeutic approach for AD, but no such disease-modifying agents have achieved clinical validation. Certain proteases are responsible for the catabolism of brain A beta in vivo, and some experimental evidence suggests they could be used as therapeutic tools to reduce A beta levels in AD. The objective of this study was to determine if enhancing the clearance of A beta in the brain by ex vivo gene delivery of an A beta-degrading protease can reduce amyloid plaque burden. Methods and Findings We generated a secreted form of the A beta-degrading protease neprilysin, which significantly lowers the levels of naturally secreted A beta in cell culture. We then used an ex vivo gene delivery approach utilizing primary fibroblasts to introduce this soluble protease into the brains of beta-amyloid precursor protein ( APP) transgenic mice with advanced plaque deposition. Brain examination after cell implantation revealed robust clearance of plaques at the site of engraftment ( 72% reduction, p = 0.0269), as well as significant reductions in plaque burden in both the medial and lateral hippocampus distal to the implantation site ( 34% reduction, p 0.0020; and 55% reduction, p = 0.0081, respectively). Conclusions Ex vivo gene delivery of an A beta-degrading protease reduces amyloid plaque burden in transgenic mice expressing human APP. These results support the use of A beta-degrading proteases as a means to therapeutically lower A beta levels and encourage further exploration of ex vivo gene delivery for the treatment of Alzheimer disease.