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

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-beta (A beta) challenge. One behavioral aspect of cognitive reserve in mice is the capacity to cope with A beta-associated stereotypies by switching to increasingly effective navigational search strategies in he Morris water maze. To explore inherent sex differences in this paradigm, however, we require an A beta PP mouse model wherein behavioral flexibility is impaired earlier in females than males despite equivalent A beta load. Here, we show that when F1 C57Bl/6xC3H/HeJ TgCRND8 mice are placed on C57Bl/6 background, N5 Tg males and females exhibit equivalent A beta 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 pde6b(rd1) mutation that impairs visual acuity and that the estrous cycle is not disrupted on this genetic background. At 5.3 months of age, Tg males, but not females, compensate for A beta-associated stereotypic behaviors (i.e., hyperactive tight circling) by alternating navigational search strategies and adopting increasingly productive spatial search strategies. Females fail to overcome A beta-associated stereotypies and do not efficiently switch from systematic to spatial learning strategies. Together, these data identify a novel A beta PP mouse model that can be used for preclinical testing of interventions targeting sexual dimorphisms in behavioral indices of cognitive reserve.