A TgCRND8 Mouse Model of Alzheimer’s Disease Exhibits Sexual Dimorphisms in Behavioral Indices of Cognitive Reserve

Article type: Research Article

Authors: Granger, Matthew W.^a | Franko, Bettina^a | Taylor, Matthew W.^a | Messier, Claude^b | George-Hyslop, Peter St.^c | Bennett, Steffany A.L.^{a; *}

Affiliations: [a] Neural Regeneration Laboratory, Ottawa Institute of Systems Biology, Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, ON, Canada | [b] School of Psychology, University of Ottawa, Ottawa, ON, Canada | [c] 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

Correspondence: [*] Correspondence to: Dr. Steffany A.L. Bennett, Neural Regeneration Laboratory and Ottawa Institute of Systems Biology, Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, 451 Smyth Rd., Ottawa, ON, K1H 8M5, Canada. Tel.: +1 613 562 5800/Ext. 8372; Fax: +1 613 562 5452; E-mail: [email protected].

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.

Keywords: Alzheimer’s disease, amyloid-β cognitive reserve, learning, memory, Morris water maze, search strategy, stereotypy, transgenic mouse, visual acuity

DOI: 10.3233/JAD-150587

Journal: Journal of Alzheimer's Disease, vol. 51, no. 3, pp. 757-773, 2016