NEPRILYSIN IS THE MAJOR ENZYME TO DEGRADE EXTRACELLULAR Aβ IN NOVEL AD ANIMAL MODELS

Abstract

Alzheimer's disease (AD) is the most common cause of dementia, which is pathologically characterized by the presence of senile plaques composed of amyloid β peptide (Aβ). In sporadic AD, it is hypothesized that an age-related decrease in extracellular Aβ catabolism causes Aβ accumulation. Neprilysin (NEP) and insulin degrading enzyme (IDE) are two major candidates considered to degrade extracellular Aβ in brain. They have, however, never been compared to each other in a side-by-side manner in vivo. In order to achieve objective comparison, we crossbred our single App knock-in mice, AppNL-F mice (NL-F mice) with NEP-knockout (KO) and IDE-KO mice. We observed an increase in the insoluble Aβ42 in NL-F x NEP-KO mice and, by contrast, a decrease in NL-F x IDE-KO mice by ELISA. NEP deficiency significantly increased pathological Aβ deposition in NL-F mice, whereas IDE deficiency decreased Aβ deposition. Expression of NEP was increased in NL-F x IDE-KO mice compared to NL-F mice, suggesting that the decrease of Aβ in NL-F x IDE-KO mice was likely a consequence of compensatory NEP upregulation. Expression of presenilin 1, BACE-1 and C-terminal fragment-β (CTF-β) remained unchanged in NL-F x IDE-KO mice, indicating that the decrease of Aβ in the double mutant mice was not due to alteration of intracellular APP processing. These observations establish NEP as the major Aβ-degrading enzyme in vivo. We conclude that NEP can become an ideal therapeutic target for reducing Aβ burdens in the preclinical stage of AD patients and that our new generation AD mice are relevant models for AD prevention study. Using a similar strategy, we are now trying to generate a novel non-human primate model of AD.