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  1. Article ; Online: MECP2 Increases the Pro-Inflammatory Response of Microglial Cells and Phosphorylation at Serine 423 Regulates Neuronal Gene Expression upon Neuroinflammation

    Rebekka Wittrahm / Mari Takalo / Mikael Marttinen / Teemu Kuulasmaa / Petra Mäkinen / Susanna Kemppainen / Henna Martiskainen / Tuomas Rauramaa / Ian Pike / Ville Leinonen / Teemu Natunen / Annakaisa Haapasalo / Mikko Hiltunen

    Cells, Vol 10, Iss 860, p

    2021  Volume 860

    Abstract: Methyl-CpG-binding protein 2 (MECP2) is a critical transcriptional regulator for synaptic function. Dysfunction of synapses, as well as microglia-mediated neuroinflammation, represent the earliest pathological events in Alzheimer’s disease (AD). Here, ... ...

    Abstract Methyl-CpG-binding protein 2 (MECP2) is a critical transcriptional regulator for synaptic function. Dysfunction of synapses, as well as microglia-mediated neuroinflammation, represent the earliest pathological events in Alzheimer’s disease (AD). Here, expression, protein levels, and activity-related phosphorylation changes of MECP2 were analyzed in post-mortem human temporal cortex. The effects of wild type and phosphorylation-deficient MECP2 variants at serine 423 (S423) or S80 on microglial and neuronal function were assessed utilizing BV2 microglial monocultures and co-cultures with mouse cortical neurons under inflammatory stress conditions. MECP2 phosphorylation at the functionally relevant S423 site nominally decreased in the early stages of AD-related neurofibrillary pathology in the human temporal cortex. Overexpression of wild type MECP2 enhanced the pro-inflammatory response in BV2 cells upon treatment with lipopolysaccharide (LPS) and interferon-γ (IFNγ) and decreased BV2 cell phagocytic activity. The expression of the phosphorylation-deficient MECP2-S423A variant, but not S80A, further increased the pro-inflammatory response of BV2 cells. In neurons co-cultured with BV2 cells, the MECP2-S423A variant increased the expression of several genes, which are important for the maintenance and protection of neurons and synapses upon inflammatory stress. Collectively, functional analyses in different cellular models suggest that MECP2 may influence the inflammatory response in microglia independently of S423 and S80 phosphorylation, while the S423 phosphorylation might play a role in the activation of neuronal gene expression, which conveys neuroprotection under neuroinflammation-related stress.
    Keywords Alzheimer’s disease ; MECP2 ; microglia ; neuroinflammation ; post-translational modifications ; synaptic markers ; Biology (General) ; QH301-705.5
    Subject code 571
    Language English
    Publishing date 2021-04-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article ; Research data: (with research data) Negative Frequency-Dependent Selection of Sexually Antagonistic Alleles in Myodes glareolus

    Mokkonen, Mikael / Esa Koskela / Hanna Kokko / Henna Martiskainen / Jussi Lehtonen / Suzanne C. Mills / Tapio Mappes

    Science. 2011 Nov. 18, v. 334, no. 6058

    2011  

    Abstract: Sexually antagonistic genetic variation, where optimal values of traits are sex-dependent, is known to slow the loss of genetic variance associated with directional selection on fitness-related traits. However, sexual antagonism alone is not sufficient ... ...

    Abstract Sexually antagonistic genetic variation, where optimal values of traits are sex-dependent, is known to slow the loss of genetic variance associated with directional selection on fitness-related traits. However, sexual antagonism alone is not sufficient to maintain variation indefinitely. Selection of rare forms within the sexes can help to conserve genotypic diversity. We combined theoretical models and a field experiment with Myodes glareolus to show that negative frequency-dependent selection on male dominance maintains variation in sexually antagonistic alleles. In our experiment, high-dominance male bank voles were found to have low-fecundity sisters, and vice versa. These results show that investigations of sexually antagonistic traits should take into account the effects of social interactions on the interplay between ecology and evolution, and that investigations of genetic variation should not be conducted solely under laboratory conditions.
    Keywords alleles ; Clethrionomys glareolus ; ecology ; evolution ; field experimentation ; genetic variance ; genetic variation ; males ; models ; sisters ; social behavior
    Language English
    Dates of publication 2011-1118
    Size p. 972-974.
    Publishing place American Association for the Advancement of Science
    Document type Article ; Research data
    ZDB-ID 128410-1
    ISSN 1095-9203 ; 0036-8075 ; 0036-8075
    ISSN (online) 1095-9203
    ISSN 0036-8075
    DOI 10.1126/science.1208708
    Database NAL-Catalogue (AGRICOLA)

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  3. Article ; Online: Effects of NR1H3 genetic variation on the expression of liver X receptor α and the progression of Alzheimer's disease.

    Teemu Natunen / Henna Martiskainen / Timo Sarajärvi / Seppo Helisalmi / Juha-Pekka Pursiheimo / Jayashree Viswanathan / Marjo Laitinen / Petra Mäkinen / Tarja Kauppinen / Tuomas Rauramaa / Ville Leinonen / Irina Alafuzoff / Annakaisa Haapasalo / Hilkka Soininen / Mikko Hiltunen

    PLoS ONE, Vol 8, Iss 11, p e

    2013  Volume 80700

    Abstract: Alzheimer's disease (AD) has been postulated to involve defects in the clearance of amyloid-β (Aβ). Activation of liver X receptor α (LXRα) increases the expression of apolipoprotein E (ApoE) as well as cholesterol transporters ABCA1 and ABCG1, leading ... ...

    Abstract Alzheimer's disease (AD) has been postulated to involve defects in the clearance of amyloid-β (Aβ). Activation of liver X receptor α (LXRα) increases the expression of apolipoprotein E (ApoE) as well as cholesterol transporters ABCA1 and ABCG1, leading to augmented clearance of Aβ. We have previously shown that the C allele of rs7120118 in the NR1H3 gene encoding LXRα reduces the risk of AD. Here, we wanted to assess whether the rs7120118 variation affects the progression of AD and modulates the expression of NR1H3 and its downstream targets APOE, ABCA1 and ABCG1.We utilized tissue samples from the inferior temporal cortex of 87 subjects, which were subdivided according to Braak staging into mild, moderate and severe AD groups on the basis of AD-related neurofibrillary pathology. APOE ε4 allele increased soluble Aβ42 levels in the tissue samples in a dose-dependent manner, but did not affect the expression status of APOE. In contrast, the CC genotype of rs7120118 was underrepresented in the severe group, although this result did not reach statistical significance. Also, patients with the CC genotype of rs7120118 showed significantly decreased soluble Aβ42 levels as compared to the patients with TT genotype. Although the severity of AD did not affect NR1H3 expression, the mRNA levels of NR1H3 among the patients with CT genotype of rs7120118 were significantly increased as compared to the patients with TT genotype. These results suggest that genetic variation in NR1H3 modulates the expression of LXRα and the levels of soluble Aβ42.
    Keywords Medicine ; R ; Science ; Q
    Subject code 610
    Language English
    Publishing date 2013-01-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  4. Article: High-fat diet increases tau expression in the brain of T2DM and AD mice independently of peripheral metabolic status

    Takalo, Mari / Annakaisa Haapasalo / Dorota Kaminska / Heikki Tanila / Henna Koivisto / Henna Martiskainen / Hilkka Soininen / Jussi Pihlajamäki / Kaisa M.A. Kurkinen / Markku Laakso / Mikko Hiltunen / Pasi Miettinen / Petra Mäkinen / Susanna Kemppainen / Ville Leinonen / Vinoth K.M. Khandelwal

    Journal of nutritional biochemistry. 2014 June, v. 25

    2014  

    Abstract: Alzheimer’s disease and type 2 diabetes mellitus are risk factors for each other. To investigate the effects of both genetic and high-fat-induced diabetic phenotype on the expression and exon 10 splicing of tau, we used the Alzheimer’s disease mouse ... ...

    Abstract Alzheimer’s disease and type 2 diabetes mellitus are risk factors for each other. To investigate the effects of both genetic and high-fat-induced diabetic phenotype on the expression and exon 10 splicing of tau, we used the Alzheimer’s disease mouse model (APdE9) cross-bred with the type 2 diabetes mouse model over-expressing insulin-like growth factor 2 in the pancreas. High-fat diet, regardless of the genotype, significantly induced the expression of four repeat tau mRNA and protein in the temporal cortex of female mice. The mRNA levels of three repeat tau were also significantly increased by high-fat diet in the temporal cortex, although three repeat tau expression was considerably lower as compared to four repeat tau. Moreover, high-fat diet significantly increased the mRNA ratio of four repeat tau vs. three repeat tau in the temporal cortex of these mice. All of these effects were independent of the peripheral hyperglycemia, hyperinsulinemia and insulin resistance. Increased four repeat tau and three repeat tau levels significantly associated with impaired memory and reduced rearing in the female mice. High-fat diet did not affect neuroinflammation, Akt/GSK3β signaling pathway or the expression of tau exon 10 splicing enhancers in the temporal cortex. Our study suggests that the high-fat diet independently of type 2 diabetes or Alzheimer’s disease background induces the expression and exon 10 inclusion of tau in the brain of female mice.
    Keywords Alzheimer disease ; animal models ; brain ; cortex ; exons ; females ; gene expression ; genotype ; high fat diet ; hyperglycemia ; hyperinsulinemia ; insulin resistance ; insulin-like growth factor II ; memory ; messenger RNA ; mice ; noninsulin-dependent diabetes mellitus ; pancreas ; phenotype ; rearing ; risk factors ; signal transduction
    Language English
    Dates of publication 2014-06
    Size p. 634-641.
    Publishing place Elsevier Inc.
    Document type Article
    ZDB-ID 1014929-6
    ISSN 1873-4847 ; 0955-2863
    ISSN (online) 1873-4847
    ISSN 0955-2863
    DOI 10.1016/j.jnutbio.2014.02.003
    Database NAL-Catalogue (AGRICOLA)

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    In stock of ZB MED Bonn / Germany

    Z 5044: Show issues

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