Ketamine reduces amyloid β-protein degradation by suppressing neprilysin expression in primary cultured astrocytes

Yamamoto, Naoki; Arima, Hisatomi; Naruse, Kaori; Kasahara, Rika; Taniura, Hideo; Hirate, Hiroyuki; Sugiura, T.; Suzuki, Kenji; Sobue, Kazuya

doi:10.1016/j.neulet.2013.04.016

Cited by 22 publications

(12 citation statements)

References 16 publications

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“…However, the precise role of astrocytes in Aβ clearance through the regulation of Aβ‐degrading enzymes expression remains unclear. We previously reported that ketamine, which is a general anesthetic, inhibits Aβ degradation by decreasing NEP expression in astrocytes and that leptin inhibits Aβ degradation by decreasing NEP expression in astrocytes (Yamamoto et al, ). Moreover, we found that NEP was secreted in the cultured medium of astrocytes and that leptin reduced the secretion of NEP into the astrocyte‐cultured medium (Yamamoto et al, ).…”

Section: Discussionmentioning

confidence: 99%

“…The aging‐related downregulation of Aβ‐degrading proteases has been corroborated for NEP, but not for IDE in transgenic Tg2576 mouse brains, in which the relevant feature for both proteases was shown to be astroglial upregulation in the vicinity of Aβ plaques (Apelt et al, ; Leal et al, ). Moreover, we recently reported that ketamine decreased the expression of NEP, but not IDE in cultured astrocytes, through a noncompetitive N‐methyl‐D‐aspartate receptor and leptin through the activation of extracellular signal‐regulated kinase (ERK) (Yamamoto et al, ).…”

Section: Introductionmentioning

confidence: 99%

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Simvastatin and atorvastatin facilitates amyloid β‐protein degradation in extracellular spaces by increasing neprilysin secretion from astrocytes through activation of MAPK/Erk1/2 pathways

Yamamoto

Fujii

Kasahara

et al. 2016

Glia

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One of the major neuropathological hallmarks of Alzheimer's disease (AD) is the deposition of amyloid β-protein (Aβ) in the brain. Aβ accumulation seems to arise from an imbalance between Aβ production and clearance. Neprilysin (NEP) and insulin-degrading enzyme (IDE) are the important Aβ-degrading enzymes in the brain, and deficits in their expression may promote Aβ deposition in patients with sporadic late-onset AD. Statins, which are used clinically for reducing cholesterol levels, can exert beneficial effects on AD. Therefore, we examined whether various statins are associated with Aβ degradation by inducing NEP and IDE expression, and then evaluating the relation between activation of intracellular signaling transduction, inhibition of cholesterol production, and morphological changes to astrocytes. Treating cultured rat astrocytes with simvastatin and atorvastatin significantly decreased the expression of NEP but not IDE in a concentration- and time-dependent manner. The decrease in NEP expression was a result of activation of extracellular signal-regulated kinase (ERK) but not the reduction of cholesterol synthesis pathway. This NEP reduction was achieved by the release to the extracellular space of cultured astrocytes. Furthermore, the cultured medium prepared from simvastatin- and atorvastatin-treated astrocytes significantly induced the degradation of exogenous Aβ. These results suggest that simvastatin and atorvastatin induce the increase of Aβ degradation of NEP on the extracellular of astrocytes by inducing ERK-mediated pathway activity and that these reagents regulate the differential mechanisms between the secretion of NEP, the induction of cholesterol reduction, and the morphological changes in the cultured astrocytes.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Simvastatin and atorvastatin facilitates amyloid β‐protein degradation in extracellular spaces by increasing neprilysin secretion from astrocytes through activation of MAPK/Erk1/2 pathways

Yamamoto

Fujii

Kasahara

et al. 2016

Glia

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“…As neprilysin (NEP) and the insulin-degrading enzyme (IDE) are well known proteases involved in amyloid degradation (Sudoh et al, 2002; Carty et al, 2013; Yamamoto et al, 2013), we thus measured their mRNA level in brains of young (5-day old) and older (25-day old) flies to explore why Ctr1C RNAi led to a significant increase in SDS insoluble but 70% FA soluble Aβ42 fractions. It’s interesting that we found the expression levels of potential amyloid-β degradation proteases (including NEP1-3 and IDE ) exhibited a trend of decreasing with age when Ctr1C was knocked down.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of human high-affinity copper importer Ctr1 orthologous in the nervous system of Drosophila ameliorates Aβ42-induced Alzheimer's disease–like symptoms

Lang

Fan

Wang

et al. 2013

Neurobiology of Aging

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Disruption of copper homeostasis has been implicated in Alzheimer’s disease (AD) during the last two decades; however, whether copper is a friend or a foe is controversial. Within a genetically tractable Drosophila AD model, we manipulated the expression of human high affinity copper importer orthologous in Drosophila to explore the in vivo roles of copper ions in the development of AD. We found that inhibition of Ctr1C expression by RNAi in Aβ-expressing flies significantly reduced copper accumulation in the brains of the flies as well as ameliorating neurodegeneration, enhancing climbing ability and prolonging lifespan. Interestingly, Ctr1C inhibition led to a significant increase in higher molecular weight Aβ42 forms in brain lysates, while it was accompanied by a trend of decreased expression of amyloid-β degradation proteases (including NEP1-3 and IDE) with age and reduced Cu-Aβ interaction-induced oxidative stress in Ctr1C RNAi flies. Similar results were obtained from inhibiting another copper importer Ctr1B and overexpressing a copper exporter DmATP7 in the nervous system of AD flies. These results imply that copper may play a causative role in developing AD, as either Aβ oligomers or aggregates were less toxic in a reduced copper environment or one with less copper binding. Early manipulation of brain copper uptake can have a great effect on Aβ pathology.

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“…Astrocytes express Aβ-degrading proteases, including neprilysin and insulin-degrading enzyme [140]. There is an age-related downregulation of these Aβ-degrading proteases [141], suggesting one way in which Aβ levels may increase with age.…”

Section: Aβ and Excitotoxicitymentioning

confidence: 99%

“…There is an age-related downregulation of these Aβ-degrading proteases [141], suggesting one way in which Aβ levels may increase with age. Of particular interest to the current review is recent work showing that MK-801 and ketamine, both non-competitive NMDAR antagonists, decrease the expression of neprilysin, but not insulin-degrading enzyme, resulting in decreased Aβ degradation [140]. Though the decreased neprilysin expression is associated with a reduction in p38 MAPK phosphorylation [140], the exact mechanism by which NMDAR antagonism decreases Aβ degradation is not known and warrants further investigation.…”

Section: Aβ and Excitotoxicitymentioning

confidence: 99%

The Role of the Tripartite Glutamatergic Synapse in the Pathophysiology of Alzheimer’s Disease

Rudy¹,

Hunsberger²,

Weitzner³

et al. 2015

Aging and disease

133

106

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Alzheimer's disease (AD) is the most common form of dementia in individuals over 65 years of age and is characterized by accumulation of beta-amyloid (Aβ) and tau. Both Aβ and tau alter synaptic plasticity, leading to synapse loss, neural network dysfunction, and eventually neuron loss. However, the exact mechanism by which these proteins cause neurodegeneration is still not clear. A growing body of evidence suggests perturbations in the glutamatergic tripartite synapse, comprised of a presynaptic terminal, a postsynaptic spine, and an astrocytic process, may underlie the pathogenic mechanisms of AD. Glutamate is the primary excitatory neurotransmitter in the brain and plays an important role in learning and memory, but alterations in glutamatergic signaling can lead to excitotoxicity. This review discusses the ways in which both beta-amyloid (Aβ) and tau act alone and in concert to perturb synaptic functioning of the tripartite synapse, including alterations in glutamate release, astrocytic uptake, and receptor signaling. Particular emphasis is given to the role of N-methyl-D-aspartate (NMDA) as a possible convergence point for Aβ and tau toxicity.

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Ketamine reduces amyloid β-protein degradation by suppressing neprilysin expression in primary cultured astrocytes

Cited by 22 publications

References 16 publications

Simvastatin and atorvastatin facilitates amyloid β‐protein degradation in extracellular spaces by increasing neprilysin secretion from astrocytes through activation of MAPK/Erk1/2 pathways

Simvastatin and atorvastatin facilitates amyloid β‐protein degradation in extracellular spaces by increasing neprilysin secretion from astrocytes through activation of MAPK/Erk1/2 pathways

Inhibition of human high-affinity copper importer Ctr1 orthologous in the nervous system of Drosophila ameliorates Aβ42-induced Alzheimer's disease–like symptoms

The Role of the Tripartite Glutamatergic Synapse in the Pathophysiology of Alzheimer’s Disease

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