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Gene Dosage Dependent Aggravation of the Neurological Phenotype in the 5XFAD Mouse Model of Alzheimer's Disease.
J Alzheimers Dis 2015; 45(4):1223-36JA

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.

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.

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 -