Increased expression of the lysosomal protease cathepsin S in hippocampal microglia following kainate-induced seizures

Akahoshi, Noriyuki; Murashima, Yoshiya L.; Himi, Toshiyuki; Ishizaki, Yasuki; Ishii, Isao

doi:10.1016/j.neulet.2007.10.007

Cited by 21 publications

(23 citation statements)

References 28 publications

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“…Thus, establishing the molecular pathways associated with the seizure-induced neuronal death may provide novel treatment strategies for patients with TLE. Although enhanced levels/expression of lysosomal enzymes does not always correlate with the degeneration of neurons, there is evidence that administration of kainic acid can lead to up-regulation of lysosomal enzymes in the affected regions of the brain (Hetman et al, 1995;Tominaga et al, 1998;Akahoshi et al, 2007;Ni et al, 2012). This finding is substantiated, in part, by our study which shows an increase in the expression, levels and activity of cathepsins B and D in the hippocampus of kainic acid-treated rats compared to controls.…”

Section: Discussionsupporting

confidence: 61%

“…These results suggest that cathepsins may have a role not only in normal cellular functioning but also in a variety of disorders associated with the degeneration of neurons, including TLE. Although some earlier studies have reported altered levels and/or activity of cathepsins in kainic acidinduced seizures (Hetman et al, 1995;Tominaga et al, 1998;Akahoshi et al, 2007;Ni et al, 2012), very little is known about the subcellular levels of the enzymes and their association, if any, to the degeneration of neurons. To address this issue, we measured the time-dependent alterations in the distribution, activity and cellular/subcellular levels of cathepsins B and D in the hippocampus of adult rats following systemic administration of kainic acid.…”

Section: Introductionmentioning

confidence: 99%

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Increased levels and activity of cathepsins B and D in kainate-induced toxicity

et al. 2015

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Section: Discussionsupporting

confidence: 61%

Section: Introductionmentioning

confidence: 99%

Increased levels and activity of cathepsins B and D in kainate-induced toxicity

et al. 2015

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“…Genes differentially expressed upon KCl treatment where identified by Illumina microarrays (Materials and Methods). Genes differentially expressed upon kainite treatment where derived from published microarray profiling data (Akahoshi et al, 2007; Materials and Methods). Mouse homologs (from HomoloGene; Sayers et al, 2010) of human genes that were previously reported as differentially expressed upon aging of the human brain comprised the aging sets.…”

Section: Resultsmentioning

confidence: 99%

“…Raw Affymetrix microarray mRNA profiling data for the kainate injection experiment (Akahoshi et al, 2007) was downloaded from GEO (Barrett et al, 2011; accession number GSE6388). The raw data was imported into R environment, transformed and normalized with RMA as implemented via the affy package (Gautier et al, 2004).…”

Section: Methodsmentioning

confidence: 99%

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A Neuronal Transcriptome Response Involving Stress Pathways is Buffered by Neuronal microRNAs

Manakov¹,

Morton²,

Enright³

et al. 2012

Front. Neurosci.

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A single microRNA (miRNA) can inhibit a large number of mRNA transcripts. This widespread regulatory function has been experimentally demonstrated for a number of miRNAs. However, even when a multitude of targets is confirmed, function of a miRNA is frequently interpreted through a prism of a handful arbitrarily selected “interesting” targets. In this work we first show that hundreds of transcripts with target sites for two miRNAs expressed endogenously in neurons, miR-124 and miR-434-3p, are coordinately upregulated in a variety of neuronal stresses. This creates a landscape where these two miRNAs can exert their widespread inhibitory potential on stress-induced transcripts. Next, we experimentally demonstrate that overexpression of these two miRNAs indeed significantly inhibits expression of hundreds of stress-induced transcripts, thus confirming that these transcripts are enriched in true targets of examined miRNAs. A number of miRNAs were previously shown to have important roles in the regulation of stress responses, and our results suggest that these roles should be understood in light of a wide spread activation of miRNA targets during stresses. Importantly, a popular cationic lipid transfection reagent triggers such induction of miRNA targets. Therefore, when a transfection paradigm is employed to study miRNA function, the results of such studies should be interpreted with consideration for the inadvertent induction of miRNA targets.

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Microglia in the degenerating brain are capable of phagocytosis of beads and of apoptotic cells, but do not efficiently remove PrP^Sc, even upon LPS stimulation

Hughes

Field

Perry

et al. 2010

Glia

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Despite the phagocytic machinery available to microglia the aberrant amyloid proteins produced during Alzheimer's and prion disease, amyloid-β and PrPSc, are inefficiently cleared. We have shown that microglia in the ME7 model of prion disease show morphological evidence of activation, synthesize low levels of pro-inflammatory cytokines and are primed to produce exaggerated responses to subsequent inflammatory challenges. Whether these microglia engage in significant phagocytic activity in the disease per se, or upon subsequent inflammatory challenge is not clear. In the present study we show transcriptional activation of a large number of scavenger receptors (SRs), matrix metalloproteinases (MMPs), oxidative enzymes, and cathepsins in ME7 animals. Hippocampally-injected inert latex beads (6 μm) are efficiently phagocytosed by microglia of ME7 prion-diseased animals, but not by microglia in normal animals. Stimulation of ME7 animals with systemic bacterial endotoxin (lipopolysaccharide, LPS) induced further increases in SR-A2, MMP3, and urokinase plasminogen activator receptor (uPAR) but decreased, or did not alter, transcription of most phagocytosis-related genes examined and did not enhance clearance of deposited PrPSc. Furthermore, intracerebral injection with LPS (0.5 μg) induced marked microglial production of IL-1β, robust cellular infiltration and marked apoptosis but also did not induce further clearance of PrPSc. These data indicate that microglia in the prion-diseased brain are capable of phagocytosis per se, but show limited efficacy in removing PrPSc even upon marked escalation of CNS inflammation. Furthermore, microglia/macrophages remain IL-1β-negative during phagocytosis of apoptotic cells. The data demonstrate that phagocytic activity and pro-inflammatory microglial phenotype do not necessarily correlate. © 2010 Wiley-Liss, Inc.

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Increased expression of the lysosomal protease cathepsin S in hippocampal microglia following kainate-induced seizures

Cited by 21 publications

References 28 publications

Increased levels and activity of cathepsins B and D in kainate-induced toxicity

Increased levels and activity of cathepsins B and D in kainate-induced toxicity

A Neuronal Transcriptome Response Involving Stress Pathways is Buffered by Neuronal microRNAs

Microglia in the degenerating brain are capable of phagocytosis of beads and of apoptotic cells, but do not efficiently remove PrP^Sc, even upon LPS stimulation

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Increased expression of the lysosomal protease cathepsin S in hippocampal microglia following kainate-induced seizures

Cited by 21 publications

References 28 publications

Increased levels and activity of cathepsins B and D in kainate-induced toxicity

Increased levels and activity of cathepsins B and D in kainate-induced toxicity

A Neuronal Transcriptome Response Involving Stress Pathways is Buffered by Neuronal microRNAs

Microglia in the degenerating brain are capable of phagocytosis of beads and of apoptotic cells, but do not efficiently remove PrPSc, even upon LPS stimulation

Contact Info

Product

Resources

About

Microglia in the degenerating brain are capable of phagocytosis of beads and of apoptotic cells, but do not efficiently remove PrP^Sc, even upon LPS stimulation