APP RNA splicing is not affected by differentiation of neurons and glia in culture

Paul, Gisela; Dutly, Fabrizio; Frei, Karl; Foguet, M.; Lübbert, Hermann

doi:10.1016/0014-5793(92)80706-m

Cited by 11 publications

(4 citation statements)

References 29 publications

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“…Here, we found APP to be expressed in a neuronal and plaque associated pattern as well as being present intracellularly in primary microglia. Microglial expression of APP has earlier been suggested by a variety of groups ( Haass et al, 1991 ; Paul et al, 1992 ; Banati et al, 1995 ), as well as RNAseq data showing expression of APP mRNA in microglial cells in vivo ( Keren-Shaul et al, 2017 ). The function of APP expression in microglia is currently unknown but due to its internal location it is less likely to contribute to Aβ metabolism and is more likely to act as an acute phase protein thereby being involved in the inflammatory response.…”

Section: Discussionmentioning

confidence: 92%

Diverse Protein Profiles in CNS Myeloid Cells and CNS Tissue From Lipopolysaccharide- and Vehicle-Injected APPSWE/PS1ΔE9 Transgenic Mice Implicate Cathepsin Z in Alzheimer’s Disease

Thygesen

Ilkjær

Kempf

et al. 2018

Front. Cell. Neurosci.

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Neuroinflammation, characterized by chronic activation of the myeloid-derived microglia, is a hallmark of Alzheimer’s disease (AD). Systemic inflammation, typically resulting from infection, has been linked to the progression of AD due to exacerbation of the chronic microglial reaction. However, the mechanism and the consequences of this exacerbation are largely unknown. Here, we mimicked systemic inflammation in AD with weekly intraperitoneal (i.p.) injections of APPSWE/PS1ΔE9 transgenic mice with E. coli lipopolysaccharide (LPS) from 9 to 12 months of age, corresponding to the period with the steepest increase in amyloid pathology. We found that the repeated LPS injections ameliorated amyloid pathology in the neocortex while increasing the neuroinflammatory reaction. To elucidate mechanisms, we analyzed the proteome of the hippocampus from the same mice as well as in unique samples of CNS myeloid cells. The repeated LPS injections stimulated protein pathways of the complement system, retinoid receptor activation and oxidative stress. CNS myeloid cells from transgenic mice showed enrichment in pathways of amyloid-beta clearance and elevated levels of the lysosomal protease cathepsin Z, as well as amyloid precursor protein, apolipoprotein E and clusterin. These proteins were found elevated in the proteome of both LPS and vehicle injected transgenics, and co-localized to CD11b+ microglia in transgenic mice and in primary murine microglia. Additionally, cathepsin Z, amyloid precursor protein, and apolipoprotein E appeared associated with amyloid plaques in neocortex of AD cases. Interestingly, cathepsin Z was expressed in microglial-like cells and co-localized to CD68+ microglial lysosomes in AD cases, and it was expressed in perivascular cells in AD and control cases. Taken together, our results implicate systemic LPS administration in ameliorating amyloid pathology in early-to-mid stage disease in the APPSWE/PS1ΔE9 mouse and attract attention to the potential disease involvement of cathepsin Z expressed in CNS myeloid cells in AD.

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Section: Discussionmentioning

confidence: 92%

Diverse Protein Profiles in CNS Myeloid Cells and CNS Tissue From Lipopolysaccharide- and Vehicle-Injected APPSWE/PS1ΔE9 Transgenic Mice Implicate Cathepsin Z in Alzheimer’s Disease

Thygesen

Ilkjær

Kempf

et al. 2018

Front. Cell. Neurosci.

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“…Hence, relatively higher levels of sorLA’s transcript expression in PCRA, when compared to PCRN, support the need to further our characterization of its expression in this brain compartment. This scenario may be reminiscent to the enhanced expression of AD associated molecules in the glia compartment, i.e., APOE (Beffert et al 2004; Poirier 2005) and specific APP isoforms (Gaul et al 1992), hence underscoring the need to unravel their significance and contribution to the onset-progression of the disease.…”

Section: Discussionmentioning

confidence: 99%

SorLA in Glia: Shared Subcellular Distribution Patterns with Caveolin-1

et al. 2011

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SorLA is an established sorting and trafficking protein in neurons with demonstrated relevance to Alzheimer’s disease (AD). It shares these roles with the caveolins, markers of membrane rafts microdomains. To further our knowledge on sorLA’s expression and traffic, we studied sorLA expression in various cultured glia and its relation to caveolin-1 (cav-1), a caveolar microdomain marker. RT-PCR and immunoblots demonstrated sorLA expression in rat C6 glioma, primary cultures of rat astrocytes (PCRA), and human astrocytoma 1321N1 cells. PCRA were determined to express the highest levels of sorLA’s message. Induction of differentiation of C6 cells into an astrocyte-like phenotype led to a significant decrease in sorLA’s mRNA and protein expression. A set of complementary experimental approaches establish that sorLA and cav-1 directly or indirectly interact in glia: (1) co-fractionation in light-density membrane raft fractions of rat C6 glioma, PCRA, and human 1321N1 astrocytoma cells; (2) a subcellular co-localization distribution pattern in vesicular perinuclear compartments seen via confocal imaging in C6 and PCRA; (3) additional confocal analysis in C6 cells suggesting that the perinuclear compartments correspond to their co-localization in early endosomes and the trans-Golgi; and; (4) co-immunoprecipitation data strongly supporting their direct or indirect physical interaction. These findings further establish that sorLA is expressed in glia and that it shares its subcellular distribution pattern with cav-1. A direct or indirect cav-1/sorLA interaction could modify the trafficking and sorting functions of sorLA in glia and its proposed neuroprotective role in AD.

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“…This procedure, rendering astrocytic preparation contaminated by less than 10% with other cell constituents (Hertz et al 1989 ), was used in several studies characterizing metabolic events and drug-induced responses of astrocytes, as well as aspects of astrocytic-neuronal interactions (cf. Eloqayli et al 2011 ; Gaul et al 1992 ; Nicholson and Renton 2002 ; Pan et al 2012 ; Waagepetersen et al 2000 ; White et al 2002 ). Briefly, 7-day-old C57BL6/J mice were rapidly decapitated and the brains were taken out.…”

Section: Methodsmentioning

confidence: 99%

Persistent Overexposure to N-Methyl-d-Aspartate (NMDA) Calcium-Dependently Downregulates Glutamine Synthetase, Aquaporin 4, and Kir4.1 Channel in Mouse Cortical Astrocytes

et al. 2018

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Astrocytes express N-methyl-D-aspartate (NMDA) receptor (NMDAR) but its functions in these cells are not well defined. This study shows that the sustained exposure (8-72 h) of mouse astrocytes to NMDA decreases the expression of the functional astroglia-specific proteins, glutamine synthetase (GS), and the water channel protein aquaporin-4 (AQP4) and also reduces GS activity. Similar to rat astrocytes (Obara-Michlewska et al. Neurochem Int 88:20-25, 2015), the exposure of mouse astrocytes to NMDA also decreased the expression of the inward rectifying potassium channel Kir4.1. NMDA failed to elicit the effects in those cells incubated in the absence of Ca and in those in which the GluN1 subunit of the NMDAR was silenced with GluN1 siRNA. The downregulation of GS, AQP4, and Kir4.1 observed in vitro may reflect NMDAR-mediated alterations of astrocytic functions noted in central nervous system pathologies associated with increased glutamate (Glu) release and excitotoxic tissue damage.

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APP RNA splicing is not affected by differentiation of neurons and glia in culture

Cited by 11 publications

References 29 publications

Diverse Protein Profiles in CNS Myeloid Cells and CNS Tissue From Lipopolysaccharide- and Vehicle-Injected APPSWE/PS1ΔE9 Transgenic Mice Implicate Cathepsin Z in Alzheimer’s Disease

Diverse Protein Profiles in CNS Myeloid Cells and CNS Tissue From Lipopolysaccharide- and Vehicle-Injected APPSWE/PS1ΔE9 Transgenic Mice Implicate Cathepsin Z in Alzheimer’s Disease

SorLA in Glia: Shared Subcellular Distribution Patterns with Caveolin-1

Persistent Overexposure to N-Methyl-d-Aspartate (NMDA) Calcium-Dependently Downregulates Glutamine Synthetase, Aquaporin 4, and Kir4.1 Channel in Mouse Cortical Astrocytes

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