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

Center for Neurologic Diseases, Department of Neurology, Harvard Institutes of Medicine, Room 730, Boston, MA 02115, USA.
American Journal Of Pathology (Impact Factor: 4.59). 08/2007; 171(1):241-51. DOI: 10.2353/ajpath.2007.070105
Source: PubMed


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.

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Available from: Dominic M Walsh, Jan 31, 2015
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    • "tase inhibitor , compound E which inhibits the production of soluble Aβ . The ISF Aβ levels from the microdialysate , upon compound E injection , now represent its clearance from the brain . This method has been used extensively in AD mouse models to obtain valuable information on genetic factors that affect clearance Aβ ( Cirrito et al . , 2003 ; Farris et al . , 2007 ; Sagare et al . , 2013b ; Zhao et al . , 2015 ) . Intracerebral microdialysis has also been used to obtain human ISF Aβ concentrations in patients undergoing invasive intracranial monitoring ( Brody et al . , 2008 ) . A pioneering method was recently developed to measure rates of Aβ synthesis and clearance in human subjects . After intr"
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    • "Implantation of primary fibroblast cells that express a secreted form of human NEP also significantly reduces plaque burdens in the mouse brain [18]. Consistently, the genetic ablation of NEP in mice markedly increases Aβ levels in whole brain and plasma, increases plaque burdens in the hippocampus, and leads to the development of AD-like neuropathology [19]. Lentivirus-mediated long-term expression of NEP improves behavioral performances and ameliorates neurodegenerative pathology in APP mice [20]. "
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