title: Loss of neprilysin function promotes amyloid plaque formation and causes cerebral amyloid angiopathy.
abstract: Cerebral deposition of the amyloid beta protein (Abeta), an invariant feature of Alzheimer's disease, reflects an imbalance between the rates of Abeta production and clearance. The causes of Abeta elevation in the common late-onset form of Alzheimer's disease (LOAD) are largely unknown. There is evidence that the Abeta-degrading protease neprilysin (NEP) is down-regulated in normal aging and LOAD. We asked whether a decrease in endogenous NEP levels can prolong the half-life of Abeta in vivo and promote development of the classic amyloid neuropathology of Alzheimer's disease. We examined the brains and plasma of young and old mice expressing relatively low levels of human amyloid precursor protein and having one or both NEP genes silenced. NEP loss of function 1) elevated whole-brain and plasma levels of human Abeta(40) and Abeta(42), 2) prolonged the half-life of soluble Abeta in brain interstitial fluid of awake animals, 3) raised the concentration of Abeta dimers, 4) markedly increased hippocampal amyloid plaque burden, and 5) led to the development of amyloid angiopathy. A approximately 50% reduction in NEP levels, similar to that reported in some LOAD brains, was sufficient to increase amyloid neuropathology. These findings demonstrate an important role for proteolysis in determining the levels of Abeta and Abeta-associated neuropathology in vivo and support the hypothesis that primary defects in Abeta clearance can cause or contribute to LOAD pathogenesis.
authors.affiliation: Center for Neurologic Diseases, Department of Neurology, Harvard Institutes of Medicine, Room 730, Boston, MA 02115, USA. farrisw@upmc.edu
authors.forename: Wesley
authors.initials: W
authors.lastname: Farris
authors.forename: Sonja G
authors.initials: SG
authors.lastname: Schütz
authors.forename: John R
authors.initials: JR
authors.lastname: Cirrito
authors.forename: Ganesh M
authors.initials: GM
authors.lastname: Shankar
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Sun
authors.forename: Ana
authors.initials: A
authors.lastname: George
authors.forename: Malcolm A
authors.initials: MA
authors.lastname: Leissring
authors.forename: Dominic M
authors.initials: DM
authors.lastname: Walsh
authors.forename: Wei Qiao
authors.initials: WQ
authors.lastname: Qiu
authors.forename: David M
authors.initials: DM
authors.lastname: Holtzman
authors.forename: Dennis J
authors.initials: DJ
authors.lastname: Selkoe
mesh_terms: D016229:Amyloid beta-Peptides / Q000097:blood / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000098:blood supply* / Q000378:metabolism; D016657:Cerebral Amyloid Angiopathy; D004195:Disease Models, Animal; D006207:Half-Life; D006624:Hippocampus / Q000473:pathology; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D015260:Neprilysin / Q000235:genetics*; D058225:Plaque, Amyloid / Q000737:chemistry*
chemical_list: D016229:Amyloid beta-Peptides; D015260:Neprilysin