Bibliographic
The delivery of proteases for the targeted degradation of Aβ is currently an untested therapeutic approach for AD. One such protease, neprilysin (NEP), a zinc metalloendopeptidase, has been identified as a critical Aβ-degrading enzyme in the CNS. Neprilysin has been shown to degrade Aβ monomers and in some reports Aβ oligomers in vitro. Delivering neprilysin to the CNS has been difficult to achieve; peripheral delivery of neprilysin with viral vector-mediated gene delivery, ex vivo cellular manipulation, or intravenous recombinant protein delivery failed to deliver neprilysin enzyme to the CNS. To address this problem the authors recently developed a neprilysin containing a brain-transport peptide that was able to reduce CNS Aβ and improve learning and memory in an APP Tg mouse model of AD. In this study , the authors characterize ASN12, a brain-targeted recombinant neprilysin protein, for pharmacology as well as efficacy in two Tg mouse models of AD. The authors found that the brain-targeted protein was transported across the blood-brain barrier and accumulated in the brain with a t1⁄2 of 24 h. Treatment of Tg2576 and APP TgLine 41 mice by repeated injections resulted in reduced intraneuronal Abeta , and attenuated Abeta induced neuropathology. In addition, mice treated with the brain-targeted neprilysin showed increased levels neurogenesis and improved performance in learning and memory tasks. These results suggest that ASN12 may be an effective treatment for AD and warrant further investigation in clinical trials.