Published online before print May 18, 2007

This Article Full Text (Rapid PDF) All Versions of this Article: ajpath.2007.070105v1 171/1/241    most recent Purchase Article View Shopping Cart Services Similar articles in this journal Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Farris, W. Articles by Selkoe, D. J. Search for Related Content PubMed Articles by Farris, W. Articles by Selkoe, D. J.

Copyright © 2007 American Society for Investigative Pathology
American Journal of Pathology, doi:10.2353/ajpath.2007.070105

Accepted for publication April 12, 2007.

Article

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

^@ To whom correspondence should be addressed. E-mail: farrisw{at}upmc.edu.

	Abstract

Cerebral deposition of the amyloid protein (A), an invariant feature of Alzheimer's disease, reflects an imbalance between the rates of A production and clearance. The causes of A elevation in the common late-onset form of Alzheimer's disease (LOAD) are largely unknown. There is evidence that the A-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 A 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 A₄₀ and A₄₂, 2) prolonged the half-life of soluble A in brain interstitial fluid of awake animals, 3) raised the concentration of A 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 A and A-associated neuropathology in vivo and support the hypothesis that primary defects in A clearance can cause or contribute to LOAD pathogenesis.

This article has been cited by other articles:

				M. A. Leissring The A{beta}Cs of A{beta}-cleaving Proteases J. Biol. Chem., October 31, 2008; 283(44): 29645 - 29649. [Abstract] [Full Text] [PDF]

				K. Iijima-Ando, S. A. Hearn, L. Granger, C. Shenton, A. Gatt, H.-C. Chiang, I. Hakker, Y. Zhong, and K. Iijima Overexpression of Neprilysin Reduces Alzheimer Amyloid-{beta}42 (A{beta}42)-induced Neuron Loss and Intraneuronal A{beta}42 Deposits but Causes a Reduction in cAMP-responsive Element-binding Protein-mediated Transcription, Age-dependent Axon Pathology, and Premature Death in Drosophila J. Biol. Chem., July 4, 2008; 283(27): 19066 - 19076. [Abstract] [Full Text] [PDF]

				S. S. El-Amouri, H. Zhu, J. Yu, R. Marr, I. M. Verma, and M. S. Kindy Neprilysin: An Enzyme Candidate to Slow the Progression of Alzheimer's Disease Am. J. Pathol., May 1, 2008; 172(5): 1342 - 1354. [Abstract] [Full Text] [PDF]