Dinucleotide repeat polymorphisms in the Neprilysin gene are not associated with sporadic Alzheimer's disease

Oda, Masaya; Morino, Hiroyuki; Makino, Hírofumi; Terasawa, Hideo; Izumi, Yuishin; Torii, Tsuyoshi; Sasaki, Ken; Nakamura, Shotaro; Kawakami, Hideshi

doi:10.1016/s0304-3940(02)00057-5

Cited by 32 publications

(21 citation statements)

References 13 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Our study demonstrated that Nep does have an inhibitory effect on A␤ deposition in mice, further supporting a regulatory role for this endopeptidase in AD. However, it is still unclear whether modulation of neprilysin expression or activity is intimately involved in the etiology of AD, because genetic linkage analysis has shown no correlation between the neprilysin locus and risk for development of AD (Sodeyama et al, 2001;Oda et al, 2002). The data presented for each mouse in Figure 4, b and c, were controlled internally by individually comparing the injected side with the contralateral side.…”

Section: Discussionmentioning

confidence: 99%

Neprilysin Gene Transfer Reduces Human Amyloid Pathology in Transgenic Mice

et al. 2003

View full text Add to dashboard Cite

The degenerative process of Alzheimer's disease is linked to a shift in the balance between amyloid-␤ (A␤) production, clearance, and degradation. Neprilysin has recently been implicated as a major extracellular A␤ degrading enzyme in the brain. However, there has been no direct demonstration that neprilysin antagonizes the deposition of amyloid-␤ in vivo. To address this issue, a lentiviral vector expressing human neprilysin (Lenti-Nep) was tested in transgenic mouse models of amyloidosis. We show that unilateral intracerebral injection of Lenti-Nep reduced amyloid-␤ deposits by half relative to the untreated side. Furthermore, Lenti-Nep ameliorated neurodegenerative alterations in the frontal cortex and hippocampus of these transgenic mice. These data further support a role for neprilysin in regulating cerebral amyloid deposition and suggest that gene transfer approaches might have potential for the development of alternative therapies for Alzheimer's disease.

show abstract

Section: Discussionmentioning

confidence: 99%

Neprilysin Gene Transfer Reduces Human Amyloid Pathology in Transgenic Mice

et al. 2003

View full text Add to dashboard Cite

show abstract

“…Previously, a microsatellite polymorphism in the promoter region of the neprilysin gene has been examined in the contexts of AD and cerebral amyloid angiopathy (Sodeyama et al, 2001;Oda et al, 2002;Lilius et al, 2003;Yamada et al, 2003;Sakai et al, 2004;Wood et al, 2007). The location of this polymorphism in the promoter region suggests it may be important in modulating gene expression (Haouas et al, 1995;Ishimaru and Shipp, 1995) and thus may modulate the degree of AB degradation.…”

Section: Introductionmentioning

confidence: 99%

A Neprilysin Polymorphism and Amyloid-β Plaques after Traumatic Brain Injury

Johnson

Stewart

Graham

et al. 2009

Journal of Neurotrauma

View full text Add to dashboard Cite

Traumatic brain injury (TBI) induces the rapid formation of Alzheimer's disease (AD)-like amyloid-b (AB) plaques in about 30% of patients. However, the mechanisms behind this selective plaque formation are unclear. We investigated a potential association between amyloid deposition acutely after TBI and a genetic polymorphism of the AB-degrading enzyme, neprilysin (n ¼ 81). We found that the length of the GT repeats in AB-accumulators was longer than in non-accumulators. Specifically, there was an increased risk of AB plaques for patients with more than 41 total repeats ( p < 0.0001; OR: 10.1). In addition, the presence of 22 repeats in at least one allele was independently associated with plaque deposition ( p ¼ 0.03; OR: 5.2). In contrast, the presence of 20 GT repeats in one allele was independently associated with a reduced incidence of AB deposition ( p ¼ 0.003). These data suggest a genetically linked mechanism that determines which TBI patients will rapidly form AB plaques. Moreover, these findings provide a potential genetic screening test for individuals at high risk of TBI, such as participants in contact sports and military personnel.

show abstract

“…19,20 Several genetic association studies tested for an association between neprilysin or insulysin gene variants and AD, but gave controversial results. [21][22][23][24][25] To date, the expression of ECE-1 in human brain had never been studied, and its potential role in the pathogenesis of AD had never been assessed. We have addressed this question by a combination of expression and genetic studies, and provide evidence for a protective role of ECE-1 against AD in the aging brain.…”

mentioning

confidence: 99%

Endothelin-converting enzyme-1 is expressed in human cerebral cortex and protects against Alzheimer's disease

et al. 2004

View full text Add to dashboard Cite

Cerebral accumulation of b-amyloid peptide (Ab) is a central event in the pathogenesis of Alzheimer's disease (AD). Endothelin-converting enzyme-1 (ECE-1) is a candidate Ab-degrading enzyme in brain, but its involvement in AD pathogenesis was never assessed. We first performed brain immunocytochemistry, using a monoclonal anti-ECE-1 antibody, and observed neuronal ECE-1 expression in various cortical regions of nondemented subjects. In the hippocampus, ECE-1 immunoreactivity showed a stereotypical pattern inversely correlated with susceptibility to Ab deposition, further suggesting a physiological role in Ab clearance. In order to undertake a genetic association study, we identified a functional genetic variant (ECE1B C-338A) located in a regulatory region of the ECE1 gene. We showed that the A allele is associated with increased transcriptional activity in promoter-reporter gene assays and with increased ECE-1 mRNA expression in human neocortex. In a case-control study involving 401 patients with late-onset AD and 461 aged controls, we found that homozygous carriers of the A allele had a reduced risk of AD (OR ¼ 0.47, 95% CI 0.25-0.88). This finding was strengthened by the analysis of two other genetic variants of the ECE1 gene, which showed that the genetic association is extended over at least 13 kilobases of the gene sequence. Our results suggest that ECE-1 expression in brain may be critical for cortical Ab clearance and offer new potential targets for therapeutic interventions in AD.

show abstract

Dinucleotide repeat polymorphisms in the Neprilysin gene are not associated with sporadic Alzheimer's disease

Cited by 32 publications

References 13 publications

Neprilysin Gene Transfer Reduces Human Amyloid Pathology in Transgenic Mice

Neprilysin Gene Transfer Reduces Human Amyloid Pathology in Transgenic Mice

A Neprilysin Polymorphism and Amyloid-β Plaques after Traumatic Brain Injury

Endothelin-converting enzyme-1 is expressed in human cerebral cortex and protects against Alzheimer's disease

Contact Info

Product

Resources

About