Isoglutaminyl cyclase contributes to CCL2-driven neuroinflammation in Alzheimer’s disease

Hartlage‐Rübsamen, Maike; Waniek, Alexander; Meißner, Juliane; Morawski, Markus; Schilling, Stephan; Jäger, Carsten; Kleinschmidt, Martin; Cynis, Holger; Kehlen, Astrid; Arendt, Thomas; Demuth, Hans‐Ulrich; Rößner, Steffen

doi:10.1007/s00401-015-1395-2

Cited by 45 publications

(34 citation statements)

References 63 publications

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“…In addition to Gfap expression, changes in C3, Gbp2, Serping1, Ccl2, and Cxcl10 expression were demonstrated to be markers of the activation of neurotoxic astrocytes. [38][39][40] As expected, the mRNA expression levels of C3, Gfap, Ccl2, and Cxcl10 in the TMT group were increased by 436%, 516%, 495%, and 862%, respectively, compared to those in the control group (P < .01; Figure 5B,E,F,G). However, the mRNA expression F I G U R E 2 Melatonin mitigates TMT-induced hippocampal neuronal damage.…”

Section: Melatonin Suppresses the Tmtinduced Activation Of Astrocytsupporting

confidence: 77%

“…Notably, melatonin treatment simultaneously suppressed GFAP and SERPINA3N expression in the hippocampus in TMT‐treated mice (Figure A). In addition to Gfap expression, changes in C3 , Gbp2 , Serping1 , Ccl2 , and Cxcl10 expression were demonstrated to be markers of the activation of neurotoxic astrocytes . As expected, the mRNA expression levels of C3 , Gfap , Ccl2 , and Cxcl10 in the TMT group were increased by 436%, 516%, 495%, and 862%, respectively, compared to those in the control group ( P < .01; Figure B,E,F,G).…”

Section: Resultsmentioning

confidence: 99%

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Inhibition of SERPINA3N‐dependent neuroinflammation is essential for melatonin to ameliorate trimethyltin chloride–induced neurotoxicity

Liu

Hong

et al. 2019

Journal of Pineal Research

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Trimethyltin chloride (TMT) is a potent neurotoxin that causes neuroinflammation and neuronal cell death. Melatonin is a well‐known anti‐inflammatory agent with significant neuroprotective activity. Male C57BL/6J mice were intraperitoneally injected with a single dose of melatonin (10 mg/kg) before exposure to TMT (2.8 mg/kg, ip). Thereafter, the mice received melatonin (10 mg/kg, ip) once a day for another three consecutive days. Melatonin dramatically alleviated TMT‐induced neurotoxicity in mice by attenuating hippocampal neuron loss, inhibiting epilepsy‐like seizures, and ameliorating memory deficits. Moreover, melatonin markedly suppressed TMT‐induced neuroinflammatory responses and astrocyte activation, as shown by a decrease in inflammatory cytokine production as well as the downregulation of neurotoxic reactive astrocyte phenotype markers. Mechanistically, serine peptidase inhibitor clade A member 3N (SERPINA3N) was identified as playing a central role in the protective effects of melatonin based on quantitative proteome and bioinformatics analysis. Most importantly, melatonin significantly suppressed TMT‐induced SERPINA3N upregulation at both the mRNA and protein levels. The overexpression of Serpina3n in the mouse hippocampus abolished the protective effects of melatonin on TMT‐induced neuroinflammation and neurotoxicity. Melatonin protected cells against TMT‐induced neurotoxicity by inhibiting SERPINA3N‐mediated neuroinflammation. Melatonin may be a promising and practical agent for reducing TMT‐induced neurotoxicity in clinical practice.

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Section: Melatonin Suppresses the Tmtinduced Activation Of Astrocytsupporting

confidence: 77%

Section: Resultsmentioning

confidence: 99%

Inhibition of SERPINA3N‐dependent neuroinflammation is essential for melatonin to ameliorate trimethyltin chloride–induced neurotoxicity

Liu

Hong

et al. 2019

Journal of Pineal Research

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“…[11] To test the toxicity of the fibril preparationsg enerated from differentA b peptides on mouse primary neurons and primary astrocytes, al actated ehydrogenase (LDH) assay was performed. [12] The relative cell death was determined by calculating the maximum cell death (induced by H 2 O 2 lysis) and corrected for standard culture conditions. In general, toxicityo f Ab peptides was more pronounced in neurons than in astrocytes ( Figure 1D and E).…”

Section: Resultsmentioning

confidence: 99%

“…[23] Toxicity:P rimary neuronal and astroglial cultures were established from C57/Bl6 mice and grown under standard conditions. [12] Briefly, primary neuronal cell cultures were derived from fetal mouse brain at gestation day 16. Astrocyte-rich primary cell cultures were derived from brains of newborn mice.…”

Section: Methodsmentioning

confidence: 99%

Pyroglutamate‐Modified Amyloid β (11‐ 40) Fibrils Are More Toxic than Wildtype Fibrils but Structurally Very Similar

Scheidt

Adler

Zeitschel

et al. 2017

Chemistry A European J

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The morphology, structure, and dynamics of mature amyloid β (Aβ) fibrils formed by the Aβ variant, which is truncated at residue 11 and chemically modified by enzymatic pyroglutamate formation (pGlu -Aβ(11-40)), was studied along with the investigation of the toxicity of these Aβ variants to neurons and astrocytes. The fibrils of pGlu -Aβ (11-40) were more toxic than wildtype Aβ (1-40) and the longer pGlu3-Aβ (3-40) especially at higher concentration, whereas the overall morphology was quite similar. The secondary structure of pGlu -Aβ (11-40) fibrils shows the typical two β-strands connected by a short turn as known for mature fibrils of Aβ (1-40) and also pGlu -Aβ (3-40). Further insights into tertiary contacts exhibit some similarities of pGlu -Aβ (11-40) fibrils with wildtype Aβ (1-40), but also a so far not described contact between Gly and Ile . This highlights the biological importance of chemical modifications on the molecular structure of Aβ.

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“…The preparation and cultivation of neural primary cells was conducted according to a modified method from Löffner, Lohmann, Walckhoff, Walter, and Hamprecht () as described in Hartlage‐Rübsamen et al (). Briefly, fetuses of Tg2576 mice rom gestation day 16 of Tg2576 mice were prepared, individually genotyped and cultured.…”

Section: Methodsmentioning

confidence: 99%

Defined astrocytic expression of human amyloid precursor protein in Tg2576 mouse brain

Heiland

Zeitschel

Puchades

et al. 2018

Glia

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Transgenic Tg2576 mice expressing human amyloid precursor protein (hAPP) with the Swedish mutation are among the most frequently used animal models to study the amyloid pathology related to Alzheimer's disease (AD). The transgene expression in this model is considered to be neuron‐specific. Using a novel hAPP‐specific antibody in combination with cell type‐specific markers for double immunofluorescent labelings and laser scanning microscopy, we here report that—in addition to neurons throughout the brain—astrocytes in the corpus callosum and to a lesser extent in neocortex express hAPP. This astrocytic hAPP expression is already detectable in young Tg2576 mice before the onset of amyloid pathology and still present in aged Tg2576 mice with robust amyloid pathology in neocortex, hippocampus, and corpus callosum. Surprisingly, hAPP immunoreactivity in cortex is restricted to resting astrocytes distant from amyloid plaques but absent from reactive astrocytes in close proximity to amyloid plaques. In contrast, neither microglial cells nor oligodendrocytes of young or aged Tg2576 mice display hAPP labeling. The astrocytic expression of hAPP is substantiated by the analyses of hAPP mRNA and protein expression in primary cultures derived from Tg2576 offspring. We conclude that astrocytes, in particular in corpus callosum, may contribute to amyloid pathology in Tg2576 mice and thus mimic this aspect of AD pathology.

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Isoglutaminyl cyclase contributes to CCL2-driven neuroinflammation in Alzheimer’s disease

Cited by 45 publications

References 63 publications

Inhibition of SERPINA3N‐dependent neuroinflammation is essential for melatonin to ameliorate trimethyltin chloride–induced neurotoxicity

Inhibition of SERPINA3N‐dependent neuroinflammation is essential for melatonin to ameliorate trimethyltin chloride–induced neurotoxicity

Pyroglutamate‐Modified Amyloid β (11‐ 40) Fibrils Are More Toxic than Wildtype Fibrils but Structurally Very Similar

Defined astrocytic expression of human amyloid precursor protein in Tg2576 mouse brain

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