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No influence of amyloid--degrading neprilysin activity on prion pathogenesis

Markus Glatzel^1,

M. Hasan Mohajeri^2,

¹ Institute of Neuropathology, University Hospital of Zürich, Schmelzbergstrasse 12, CH-8091 Zürich, Switzerland
² Division of Psychiatry Research, University of Zürich, August Forel Str. 1, CH-8008 Zürich, Switzerland
³ Pulmonary Division, Children's Hospital, Harvard Medical School, Boston, USA

Correspondence
Markus Glatzel
markus.glatzel{at}usz.ch
Adriano Aguzzi
adriano{at}pathol.unizh.ch

Transmissible spongiform encephalopathies are characterized by the accumulation of PrP^Sc, a protease-resistant form of a host-derived protein termed PrP^C. Substantial evidence indicates that PrP^Sc represents an essential component of the infectious agent, which is termed prion. The accumulation of PrP^Sc within the central nervous system of prion-infected organisms is a dynamic process that is regulated both by production and by clearance of PrP^Sc. Although several proteases have been implicated in proteolysis of PrP^C, the mechanisms underlying proteolysis of PrP^Sc remain unclear. Here, it was investigated whether neprilysin, a metalloprotease known to degrade extracellular amyloidogenic proteins such as amyloid-, plays a role in prion pathogenesis in vivo. As neprilysin has a broad substrate specificity and is localized subcellularly in the vicinity of PrP, it represents a plausible candidate for prion degradation. Prions were therefore administered to mice lacking or overexpressing neprilysin in brain. However, the gene dosage of neprilysin did not modulate accumulation of PrP^Sc in brain. Also, incubation times and clinical course of prion disease, as well as brain infectivity titres at terminal stage, were unaffected. These data rule out neprilysin as a major modulator of PrP^Sc accumulation and prion pathogenesis.

These authors contributed equally to this work.