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

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.

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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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    ABSTRACT: Amyloid beta (Aβ) homeostasis in the brain is governed by its production and clearance mechanisms. An imbalance in this homeostasis results in pathological accumulations of cerebral Aβ, a characteristic of Alzheimer’s disease (AD). While Aβ may be cleared by several physiological mechanisms, a major route of Aβ clearance is the vascular-mediated removal of Aβ from the brain across the blood-brain barrier (BBB). Here, we discuss the role of the predominant Aβ clearance protein—low-density lipoprotein receptor-related protein 1 (LRP1)—in the efflux of Aβ from the brain. We also outline the multiple factors that influence the function of LRP1-mediated Aβ clearance, such as its expression, shedding, structural modification and transcriptional regulation by other genes. Finally, we summarize approaches aimed at restoring LRP1-mediated Aβ clearance from the brain
    Frontiers in Aging Neuroscience 07/2015; 7(00136). DOI:10.3389/fnagi.2015.00136 · 4.00 Impact Factor
    • "There is evidence suggesting that the soluble oligomers have a higher neurotoxicity than monomers and are responsible for synaptic degradation [7e9]. Several enzymes that are known to hydrolyze amyloid beta have also been shown to regulate the endogenous amyloid beta concentration, such as neprilysin (NEP) [10] [11], endothelin converting enzyme (ECE)-1 [12] [13] and insulin degrading enzyme (IDE) [14] [15]. The Ab degradation has been determined by sandwich enzymelinked immunosorbent assay (ELISA) or western blot methods, in which the decline in Ab 1-42 and/or Ab 1-40 concentration over time is measured [14] [16]. "
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    ABSTRACT: Deposition of insoluble amyloid plaques is one of the known hallmarks of Alzheimer's disease. Amyloid beta 1-42 is the main component in these plaques, and the soluble oligomers of this peptide are believed to contribute to synaptic degradation and dementia. Enzymatic hydrolysis of amyloid beta is important to keep its tissue concentration low to avoid oligomerization. We have employed four enzymes involved in in vivo degradation of amyloid beta, to identify amyloid beta 1-42 hydrolysis products in vitro. Liquid chromatography coupled to (high resolution) mass spectrometry was used to identify the proteolysis products. Novel cleavage sites were discovered for all four enzymes. For each enzyme, the peptide was incubated for several different periods from 0.5 to 210 min, and the proteolysis products from each period were characterized. Thus, both the initial cleavage sites and the full degradation profiles were revealed. Knowledge about the fate of amyloid beta is important to better understand the mechanism underlying Alzheimer`s disease, and the reported proteolysis products can be used as targets in future investigations on amyloid beta clearance.
    Biochimie 07/2014; 105:216-220. DOI:10.1016/j.biochi.2014.06.023 · 2.96 Impact Factor
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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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    ABSTRACT: Nuclear inclusion a (NIa) of turnip mosaic virus is a cytosolic protease that cleaves amyloid β (Aβ) when heterologously overexpressed. Lentivirus-mediated expression of NIa in the brains of APP(sw)/PS1 mice significantly reduces cerebral Aβ levels and plaque depositions, and improves behavioral deficits. Here, the effects of NIa and neprilysin (NEP), a well-known Aβ-cleaving protease, on oligomeric Aβ-induced cell death were evaluated. NIa cleaved monomeric and oligomeric Aβ at a similar rate, whereas NEP only cleaved monomeric Aβ. Oligomeric Aβ-induced cytotoxicity and mitochondrial dysfunction were significantly ameliorated by NIa, but not by NEP. Endocytosed fluorescently-labeled Aβ localized to mitochondria, and this was significantly reduced by NIa, but not by NEP. These data suggest that NIa may exerts its protective roles by degrading Aβ and thus preventing mitochondrial deposition of Aβ.
    PLoS ONE 06/2014; 9(6):e98650. DOI:10.1371/journal.pone.0098650 · 3.23 Impact Factor
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