Published online before print May 18, 2007

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(American Journal of Pathology. 2007;171:241-251.)
© 2007 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2007.070105

Loss of Neprilysin Function Promotes Amyloid Plaque Formation and Causes Cerebral Amyloid Angiopathy

Wesley Farris^*, Sonja G. Schütz^*, John R. Cirrito, Ganesh M. Shankar^*, Xiaoyan Sun, Ana George^*, Malcolm A. Leissring^¶, Dominic M. Walsh^||, Wei Qiao Qiu, David M. Holtzman^** and Dennis J. Selkoe^*

From the Center for Neurologic Diseases,^* Department of Neurology, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts; the Departments of Neurology, Psychiatry, Molecular Biology and Pharmacology and Hope Center for Neurological Disorders,^** Washington University Medical School, St. Louis, Missouri; the Department of Psychiatry, New England Medical Center and Tufts University School of Medicine, Boston, Massachusetts; The Scripps Research Institute,^¶ Scripps Florida, Jupiter, Florida; the Laboratory for Neurodegenerative Research,|| Conway Institute, University College Dublin, Republic of Ireland; and the Pittsburgh Institute for Neurodegenerative Diseases, Department of Neurology, University of Pittsburgh School of Medicine, and Geriatric Research, Education and Clinical Center, VA Pittsburgh Healthcare System, Pittsburgh, Pennsylvania

Cerebral deposition of the amyloid ß protein (Aß), an invariant feature of Alzheimer’s disease, reflects an imbalance between the rates of Aß production and clearance. The causes of Aß elevation in the common late-onset form of Alzheimer’s disease (LOAD) are largely unknown. There is evidence that the Aß-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 Aß 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 Aß₄₀ and Aß₄₂, 2) prolonged the half-life of soluble Aß in brain interstitial fluid of awake animals, 3) raised the concentration of Aß dimers, 4) markedly increased hippocampal amyloid plaque burden, and 5) led to the development of amyloid angiopathy. A 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 Aß and Aß-associated neuropathology in vivo and support the hypothesis that primary defects in Aß clearance can cause or contribute to LOAD pathogenesis.

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