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Gene Dosage Dependent Aggravation of the Neurological Phenotype in the 5XFAD Mouse Model of Alzheimer's Disease.

Abstract

In the present report, we extend previous findings in the 5XFAD mouse model with regard to a characterization of behavioral deficits and neuropathological alterations. We demonstrate that these mice develop a robust age-dependent motor phenotype and spatial reference memory deficits when bred to homozygosity, leading to a strongly reduced age of onset of behavioral symptoms. At postnatal day sixteen, abundant AβPP was detected in subiculum and cortical pyramidal neurons. From six weeks on, intraneuronal Aβ could be detected which was much more abundant in homozygous mice. The same gene-dosage effect was seen on memory and motor deficits. While at 2 months of age neither heterozygous nor homozygous 5XFAD mice show any neurological phenotype except for alterations in anxiety behavior, at 5 months they were clearly evident. Interestingly, despite abundant motor deficiencies, homozygous 5XFAD mice were able to perform the acquisition training of the Morris water maze task with no difference in the swimming performance between the groups. Therefore the aggravated spatial memory and spatial reference memory deficits of the homozygous mice correlated with the elevated soluble and insoluble Aβ levels. Homozygous 5XFAD mice represent a model with several advantages in comparison to the heterozygous mice, developing amyloid pathology much more rapidly together with a neurological phenotype. These advantages allow reducing the number of animals for Alzheimer's disease research.

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  • Authors+Show Affiliations

    ,

    Division of Molecular Psychiatry, Department of Psychiatry and Psychotherapy, University Medical Center (UMG), Georg-August-University, Göttingen, Germany.

    ,

    Division of Molecular Psychiatry, Department of Psychiatry and Psychotherapy, University Medical Center (UMG), Georg-August-University, Göttingen, Germany.

    ,

    Molecular Neuropathology Group, Department of Neuropathology, Heinrich-Heine-University, Düsseldorf, Germany.

    ,

    Division of Molecular Psychiatry, Department of Psychiatry and Psychotherapy, University Medical Center (UMG), Georg-August-University, Göttingen, Germany.

    ,

    Molecular Neuropathology Group, Department of Neuropathology, Heinrich-Heine-University, Düsseldorf, Germany.

    Division of Molecular Psychiatry, Department of Psychiatry and Psychotherapy, University Medical Center (UMG), Georg-August-University, Göttingen, Germany.

    Source

    MeSH

    Age of Onset
    Aging
    Alzheimer Disease
    Amyloid beta-Peptides
    Amyloid beta-Protein Precursor
    Animals
    Body Weight
    Brain
    Disease Models, Animal
    Gene Dosage
    Humans
    Maze Learning
    Mice, Inbred C57BL
    Mice, Transgenic
    Motor Activity
    Neurons
    Phenotype
    Presenilin-1
    Spatial Memory

    Pub Type(s)

    Journal Article
    Research Support, Non-U.S. Gov't

    Language

    eng

    PubMed ID

    25697701

    Citation

    Richard, Bernhard Clemens, et al. "Gene Dosage Dependent Aggravation of the Neurological Phenotype in the 5XFAD Mouse Model of Alzheimer's Disease." Journal of Alzheimer's Disease : JAD, vol. 45, no. 4, 2015, pp. 1223-36.
    Richard BC, Kurdakova A, Baches S, et al. Gene Dosage Dependent Aggravation of the Neurological Phenotype in the 5XFAD Mouse Model of Alzheimer's Disease. J Alzheimers Dis. 2015;45(4):1223-36.
    Richard, B. C., Kurdakova, A., Baches, S., Bayer, T. A., Weggen, S., & Wirths, O. (2015). Gene Dosage Dependent Aggravation of the Neurological Phenotype in the 5XFAD Mouse Model of Alzheimer's Disease. Journal of Alzheimer's Disease : JAD, 45(4), pp. 1223-36. doi:10.3233/JAD-143120.
    Richard BC, et al. Gene Dosage Dependent Aggravation of the Neurological Phenotype in the 5XFAD Mouse Model of Alzheimer's Disease. J Alzheimers Dis. 2015;45(4):1223-36. PubMed PMID: 25697701.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Gene Dosage Dependent Aggravation of the Neurological Phenotype in the 5XFAD Mouse Model of Alzheimer's Disease. AU - Richard,Bernhard Clemens, AU - Kurdakova,Anastasiia, AU - Baches,Sandra, AU - Bayer,Thomas A, AU - Weggen,Sascha, AU - Wirths,Oliver, PY - 2015/2/21/entrez PY - 2015/2/24/pubmed PY - 2016/3/10/medline KW - 5XFAD KW - Amyloid KW - axonal degeneration KW - behavior KW - intraneuronal Aβ KW - motor deficit KW - spatial memory KW - transgenic mice SP - 1223 EP - 36 JF - Journal of Alzheimer's disease : JAD JO - J. Alzheimers Dis. VL - 45 IS - 4 N2 - In the present report, we extend previous findings in the 5XFAD mouse model with regard to a characterization of behavioral deficits and neuropathological alterations. We demonstrate that these mice develop a robust age-dependent motor phenotype and spatial reference memory deficits when bred to homozygosity, leading to a strongly reduced age of onset of behavioral symptoms. At postnatal day sixteen, abundant AβPP was detected in subiculum and cortical pyramidal neurons. From six weeks on, intraneuronal Aβ could be detected which was much more abundant in homozygous mice. The same gene-dosage effect was seen on memory and motor deficits. While at 2 months of age neither heterozygous nor homozygous 5XFAD mice show any neurological phenotype except for alterations in anxiety behavior, at 5 months they were clearly evident. Interestingly, despite abundant motor deficiencies, homozygous 5XFAD mice were able to perform the acquisition training of the Morris water maze task with no difference in the swimming performance between the groups. Therefore the aggravated spatial memory and spatial reference memory deficits of the homozygous mice correlated with the elevated soluble and insoluble Aβ levels. Homozygous 5XFAD mice represent a model with several advantages in comparison to the heterozygous mice, developing amyloid pathology much more rapidly together with a neurological phenotype. These advantages allow reducing the number of animals for Alzheimer's disease research. SN - 1875-8908 UR - https://www.unboundmedicine.com/medline/citation/25697701/Gene_Dosage_Dependent_Aggravation_of_the_Neurological_Phenotype_in_the_5XFAD_Mouse_Model_of_Alzheimer's_Disease_ L2 - https://content.iospress.com/openurl?genre=article&id=doi:10.3233/JAD-143120 DB - PRIME DP - Unbound Medicine ER -