Background
Understanding the mechanisms of amyloid- protein (A) production and clearance in the brain has been
essential to elucidating the etiology of Alzheimer disease (AD). Chronically decreasing brain A 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 in vivo, and some experimental evidence suggests they could be used as therapeutic tools to reduce A levels in AD. The objective of this study was to determine if enhancing the clearance of A in the brain by ex vivo gene delivery of an A-
degrading protease can reduce amyloid plaque burden.
Methods and Findings
We generated a secreted form of the A-degrading protease neprilysin, which significantly lowers the levels of naturally secreted A in cell culture. We then used an ex vivo gene delivery approach utilizing primary fibroblasts to introduce this soluble protease into the brains of -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-degrading protease reduces amyloid plaque burden in transgenic mice expressing human APP. These results support the use of A-degrading proteases as a means to therapeutically lower A levels and encourage further exploration of ex vivo gene delivery for the treatment of Alzheimer disease.