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The Journal of Neuroscience, January 28, 2004, 24(4):991-998; doi:10.1523/JNEUROSCI.4792-03.2004

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Neurobiology of Disease
Presynaptic Localization of Neprilysin Contributes to Efficient Clearance of Amyloid- Peptide in Mouse Brain

Nobuhisa Iwata,¹ Hiroaki Mizukami,² Keiro Shirotani,¹ Yoshie Takaki,¹ Shin-ichi Muramatsu,³ Bao Lu,⁴ Norma P. Gerard,⁴ Craig Gerard,⁴ Keiya Ozawa,² and Takaomi C. Saido¹

¹Laboratory for Proteolytic Neuroscience, RIKEN Brain Science Institute, Wako-shi, Saitama 351-0198, Japan, ²Division of Genetic Therapeutics, Center for Molecular Medicine, and ³Division of Neurology, Department of Medicine, Jichi Medical School, Tochigi 329-0498, Japan, and ⁴Department of Pediatrics and Medicine, Harvard Medical School, Boston, Massachusetts 02115

A local increase in amyloid- peptide (A) is closely associated with synaptic dysfunction in the brain in Alzheimer's disease. Here, we report on the catabolic mechanism of A at the presynaptic sites. Neprilysin, an A-degrading enzyme, expressed by recombinant adeno-associated viral vector-mediated gene transfer, was axonally transported to presynaptic sites through afferent projections of neuronal circuits. This gene transfer abolished the increase in A levels in the hippocampal formations of neprilysin-deficient mice and also reduced the increase in young mutant amyloid precursor protein transgenic mice. In the latter case, A levels in the hippocampal formation contralateral to the vector-injected side were also significantly reduced as a result of transport of neprilysin from the ipsilateral side, and in both sides soluble A was degraded more efficiently than insoluble A. Furthermore, amyloid deposition in aged mutant amyloid precursor protein transgenic mice was remarkably decelerated. Thus, presynaptic neprilysin has been demonstrated to degrade A efficiently and to retard development of amyloid pathology.

Key words: Alzheimer; axonal transport; axoplasmic transport; gene; hippocampus; presynaptic; projection; endopeptidase; amyloid- peptide; gene transfer; adeno-associated viral vector; degradation; perforant path

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Received Oct 24, 2003; revised December 2, 2003; accepted December 7, 2003.

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