title: A TgCRND8 Mouse Model of Alzheimer's Disease Exhibits Sexual Dimorphisms in Behavioral Indices of Cognitive Reserve.
abstract: Cognitive decline is sexually dimorphic in Alzheimer's disease (AD). Men show higher incidences of amnestic mild cognitive impairment yet women disproportionally phenoconvert to AD. It is hypothesized that men maintain greater cognitive reserve than women under comparable amyloid-β (Aβ) challenge. One behavioral aspect of cognitive reserve in mice is the capacity to cope with Aβ-associated stereotypies by switching to increasingly effective navigational search strategies in the Morris water maze. To explore inherent sex differences in this paradigm, however, we require an AβPP mouse model wherein behavioral flexibility is impaired earlier in females than males despite equivalent Aβ load. Here, we show that when F1 C57Bl/6×C3H/HeJ TgCRND8 mice are placed on C57Bl/6 background, N5 Tg males and females exhibit equivalent Aβ pathologies at 2, 4, 6, and 8 months of age yet females display learning and memory deficits earlier than males. We further show that this N5 line does not carry the autosomal recessive pde6brd1 mutation that impairs visual acuity and that the estrous cycle is not disrupted on this genetic background. At 5.5 months of age, Tg males, but not females, compensate for Aβ-associated stereotypic behaviors (i.e., hyperactive tight circling) by alternating navigational search strategies and adopting increasingly productive spatial search strategies. Females fail to overcome Aβ-associated stereotypies and do not efficiently switch from systematic to spatial learning strategies. Together, these data identify a novel AβPP mouse model that can be used for preclinical testing of interventions targeting sexual dimorphisms in behavioral indices of cognitive reserve.
authors.affiliation: Neural Regeneration Laboratory, Ottawa Institute of Systems Biology, Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, ON, Canada.
authors.forename: Matthew W
authors.initials: MW
authors.lastname: Granger
authors.affiliation: Neural Regeneration Laboratory, Ottawa Institute of Systems Biology, Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, ON, Canada.
authors.forename: Bettina
authors.initials: B
authors.lastname: Franko
authors.affiliation: Neural Regeneration Laboratory, Ottawa Institute of Systems Biology, Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, ON, Canada.
authors.forename: Matthew W
authors.initials: MW
authors.lastname: Taylor
authors.affiliation: School of Psychology, University of Ottawa, Ottawa, ON, Canada.
authors.forename: Claude
authors.initials: C
authors.lastname: Messier
authors.affiliation: Department of Clinical Neurosciences, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK and Tanz Centre for Research in Neurodegenerative Diseases University of Toronto, Toronto, ON, Canada.
authors.forename: Peter St
authors.initials: PS
authors.lastname: George-Hyslop
authors.affiliation: Neural Regeneration Laboratory, Ottawa Institute of Systems Biology, Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, ON, Canada.
authors.forename: Steffany A L
authors.initials: SA
authors.lastname: Bennett
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000473:pathology / Q000503:physiopathology* / Q000523:psychology*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000473:pathology / Q000503:physiopathology; D058245:Cognitive Reserve; D054707:Cyclic Nucleotide Phosphodiesterases, Type 6 / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D008297:Male; D018782:Maze Learning / Q000502:physiology; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D058225:Plaque, Amyloid / Q000235:genetics / Q000473:pathology / Q000503:physiopathology / Q000523:psychology; D011597:Psychomotor Performance / Q000502:physiology; D012727:Sex Characteristics; D065852:Spatial Memory / Q000502:physiology; D065854:Spatial Navigation / Q000502:physiology; D016019:Survival Analysis
chemical_list: C545487:APP protein, human; D016564:Amyloid beta-Protein Precursor; D054707:Cyclic Nucleotide Phosphodiesterases, Type 6; C517431:PDE6B protein, human
keywords: Alzheimer’s disease; Morris water maze; amyloid-β cognitive reserve; learning; memory; search strategy; stereotypy; transgenic mouse; visual acuity