Decreased Expression and Activity of Neprilysin in Alzheimer Disease Are Associated With Cerebral Amyloid Angiopathy

Miners, Scott; Helmond, Zoë Van; Chalmers, Katy A; Wilcock, Gordon; Love, Seth; Kehoe, Patrick Gavin

doi:10.1097/01.jnen.0000240463.87886.9a

Cited by 132 publications

(145 citation statements)

References 65 publications

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“…Neprilysin (NEP), a zincdependent metallopeptidase, serves as the major physiological Aβ-degrading enzyme (9). However, both the expression and activity of NEP decrease with age in AD brains (13,33), and the transcriptional regulatory mechanisms that regulate NEP expression are relatively unknown. In the present study, we observed the DNA methylation status of NEP gene in wild-type N2a cells (N2a/wt), which is devoid of NEP (34), and N2a cells stably expressing human Swedish mutant APP (N2a/APPswe) associated with familial early onset AD (27).…”

Section: Inhibition Of Akt/nf-κb Signaling By Cur Is Associated With mentioning

confidence: 99%

Curcumin Inhibits the AKT/NF-κB Signaling via CpG Demethylation of the Promoter and Restoration of NEP in the N2a Cell Line

Deng

Wang

et al. 2014

AAPS J

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Abstract. Curcumin (CUR), a non-toxic polyphenol from Curcuma longa, has been investigated as a potential therapy with anti-inflammatory and anti-oxidative effects for Alzheimer's disease (AD), which depicts features of chronic inflammatory environment resulting in cellular death. However, it remains largely unknown whether the anti-inflammatory effect of CUR in AD is associated with its property of CpG demethylation, which is another function of CUR with the most research interest during recent years. Neprilysin (NEP, EP24.11), a zinc-dependent metallopeptidase expressed relatively low in the brain, is emerging as a potent inhibitor of AKT/Protein Kinase B. In addition, hypermethylated promoter of NEP has been reported to be associated with decreases in NEP expression. In the present study, using bisulfite-sequencing PCR (BSP) assay, we showed that the CpG sites in NEP gene were hypermethylated both in wild-type mouse neuroblastoma N2a cells (N2a/wt) and N2a cells stably expressing human Swedish mutant amyloid precursor protein (APP) (N2a/APPswe) associated with familial early onset AD. CUR treatment induced restoration of NEP gene via CpG demethylation. This CUR-mediated upregulation of NEP expression was also concomitant with the inhibition of AKT, subsequent suppression of nuclear transcription factor-κB (NF-κB) and its downstream pro-inflammatory targets including COX-2, iNOS in N2a/APPswe cells. This study represents the first evidence on a link between CpG demethylation effect on NEP and anti-inflammation ability of CUR that may provide a novel mechanistic insight into the anti-inflammatory actions of CUR as well as new basis for using CUR as a therapeutic intervention for AD.

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Section: Inhibition Of Akt/nf-κb Signaling By Cur Is Associated With mentioning

confidence: 99%

Curcumin Inhibits the AKT/NF-κB Signaling via CpG Demethylation of the Promoter and Restoration of NEP in the N2a Cell Line

Deng

Wang

et al. 2014

AAPS J

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“…49 Although it is unknown whether the observed age-associated reduction in NEP brain levels occurs by this mechanism, it is known that NEP mRNA and protein levels are, in fact, decreased in the brains, cerebral vasculature, and cerebrospinal fluid of LOAD patients. 19,21,33,50,51 Importantly, it has also been shown that the levels of cortical NEP and vascular NEP in AD brain are inversely related to the levels of insoluble A␤ 48 and the severity of CAA, 33,52 respectively. Because brains with severe CAA had similar reductions in NEP in A␤-free and A␤-laden vessels, it seemed that the decrease in NEP was not simply secondary to CAA, suggesting that low NEP levels may have led to the vascular amyloid deposition.…”

Section: Defects In A␤ Clearance Could Be Causative Of Some Cases Of mentioning

confidence: 99%

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

Farris

Schütz

Cirrito

et al. 2007

The American Journal of Pathology

140

104

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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 halflife 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 A␤ 40 and A␤ 42 , 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 ϳ50% 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. (Am J Pathol

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“…For example, decreased expression of insulin degrading enzyme (IDE) or neprilysin -both of which are known to degrade Aβ-leads to increased accumulation of Aβ, and ultimately to AD. In contrast, overexpression of these enzymes reduces Aβ levels and attenuates Aβ-related memory deficit [16][17][18][19][20] . Together, these studies provide a compelling case for the role of Aβ aggregation in the pathogenesis of Alzheimer's disease.…”

Section: Introductionmentioning

confidence: 99%

Mutations Enhance the Aggregation Propensity of the Alzheimer’s Aβ Peptide

Kim

Hecht

2008

Journal of Molecular Biology

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Aggregation of the amyloid β peptide (Aβ) plays a key role in the molecular etiology of Alzheimer's disease. Despite the importance of this process, the relationship between the sequence of Aβ and the propensity of the peptide to aggregate has not been fully elucidated. The sequence determinants of aggregation can be revealed by probing the ability of amino acid substitutions (mutations) to increase or decrease aggregation. Numerous mutations that decrease aggregation have been isolated by laboratory-based studies. In contrast, very few mutations that increase aggregation have been reported, and most of these were isolated from rare individuals with early onset Familial Alzheimer's disease. To augment the limited data set of clinically derived mutations, we developed an artificial genetic screen to isolate novel mutations that increase aggregation propensity. The screen relies on expression in E. coli of a fusion of Aβ to green fluorescent protein (GFP). In this fusion, the ability of the GFP reporter to fold and fluoresce is inversely correlated with the aggregation propensity of the Aβ sequence. Implementation of this screen enabled the isolation of 20 mutant versions of Aβ with amino acid substitutions at 17 positions in the 42-residue sequence of Aβ. Biophysical studies of synthetic peptides corresponding to sequences isolated by the screen confirm the increased aggregation propensity and amyloidogenic behavior of the mutants. The mutations were isolated using an unbiased screen that makes no assumptions about the sequence determinants of aggregation. Nonetheless, all 16 of the most aggregating mutants contain substitutions that reduce charge and/or increase hydrophobicity. These findings provide compelling evidence supporting the hypothesis that sequence hydrophobicity is a major determinant of Aβ aggregation.

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Decreased Expression and Activity of Neprilysin in Alzheimer Disease Are Associated With Cerebral Amyloid Angiopathy

Cited by 132 publications

References 65 publications

Curcumin Inhibits the AKT/NF-κB Signaling via CpG Demethylation of the Promoter and Restoration of NEP in the N2a Cell Line

Curcumin Inhibits the AKT/NF-κB Signaling via CpG Demethylation of the Promoter and Restoration of NEP in the N2a Cell Line

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

Mutations Enhance the Aggregation Propensity of the Alzheimer’s Aβ Peptide

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