title: 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.
authors.affiliation: Division of Molecular Psychiatry, Department of Psychiatry and Psychotherapy, University Medical Center (UMG), Georg-August-University, Göttingen, Germany.
authors.forename: Bernhard Clemens
authors.initials: BC
authors.lastname: Richard
authors.affiliation: Division of Molecular Psychiatry, Department of Psychiatry and Psychotherapy, University Medical Center (UMG), Georg-August-University, Göttingen, Germany.
authors.forename: Anastasiia
authors.initials: A
authors.lastname: Kurdakova
authors.affiliation: Molecular Neuropathology Group, Department of Neuropathology, Heinrich-Heine-University, Düsseldorf, Germany.
authors.forename: Sandra
authors.initials: S
authors.lastname: Baches
authors.affiliation: Division of Molecular Psychiatry, Department of Psychiatry and Psychotherapy, University Medical Center (UMG), Georg-August-University, Göttingen, Germany.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Bayer
authors.affiliation: Molecular Neuropathology Group, Department of Neuropathology, Heinrich-Heine-University, Düsseldorf, Germany.
authors.forename: Sascha
authors.initials: S
authors.lastname: Weggen
authors.affiliation: Division of Molecular Psychiatry, Department of Psychiatry and Psychotherapy, University Medical Center (UMG), Georg-August-University, Göttingen, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Wirths
mesh_terms: D017668:Age of Onset; D000375:Aging / Q000235:genetics / Q000473:pathology; D000544:Alzheimer Disease / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001835:Body Weight / Q000235:genetics / Q000502:physiology; D001921:Brain / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D018628:Gene Dosage; D006801:Humans; D018782:Maze Learning / Q000502:physiology; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009043:Motor Activity / Q000235:genetics / Q000502:physiology; D009474:Neurons / Q000378:metabolism; D010641:Phenotype; D053764:Presenilin-1 / Q000235:genetics / Q000378:metabolism; D065852:Spatial Memory / Q000502:physiology
chemical_list: C545487:APP protein, human; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; C508853:PSEN1 protein, human; D053764:Presenilin-1
keywords: 5XFAD; Amyloid; axonal degeneration; behavior; intraneuronal Aβ; motor deficit; spatial memory; transgenic mice