CYP1B1 deiciency ameliorates learning and memory deficits caused by high fat diet in mice

Our previous study showed that Cyp1b1 deficiency could protect male mice from high fat diet (HFD) obesity. In this paper, we aim to explore the role of Cyp1b1 in HFD induced learning and memory deficits in female C57BL/6J mice.

Female Cyp1b1 knock-out (KO) and wild type (WT) mice were both randomly divided into normal chew (NC) and HFD groups. All mice were fed research diet after weaning for 24 consecutive weeks. Morris Water Maze was carried out to evaluate the spatial learning and memory. Brain lipoxidation status was evaluated by malondialdehyde (MDA) level and 4-hydroxynonenal (4-HNE)-protein adducts in mice cerebral cortex. Both activity and expression of antioxidant enzymes were determined by commercial kits and realtime RT-PCR. β-amyloid (Aβ) was detected in mice brain by immunohistochemistry. Brain derived neurotrophic factor (BDNF), synaptic plasticity protein Activity-regulated cytoskeleton-associated protein (ARC), neuronal migration and positioning gene Reelin, and Nrf2, a key transcription factor in oxidative stress, and its downstream targets heme oxygenase-1 (HO-1) and NAD(P)H dehydrogenase (quinone) (NQO-1) were measured in cerebral cortex.

Cyp1b1 deficiency mice performed better on learning and memory tests compared with WT mice after 24 weeks HFD feeding. HFD elevated brain oxidative stress, lipoxidation in mice cerebral cortex, β-amyloid deposition in hippocampus; suppressed antioxidant genes expression in cerebral cortex, and these effects were ameliorated by Cyp1b1 deletion. BDNF expression increased in Cyp1b1 deficiency mice after HFD feeding compared with WT. HFD activated Nrf2 and its target genes and Cyp1b1 deletion reversed such impact.

Cyp1b1 deficiency protects mice from HFD induced cognitive impairment. Sustained BDNF expression, reduced β-amyloid accumulation and brain oxidative stress, and Nrf2 deactivation might be the key events in mice redox system through Cyp1b1-diet interaction.