APOE4 genotype exacerbates the impact of menopause on cognition and synaptic plasticity in APOE‐TR mice

Pontifex, Matthew G., Martinsen, Anneloes, Saleh, Rasha Noureldin M., Harden, Glenn, Tejera, Noemi, Müller, Michael ORCID: https://orcid.org/0000-0002-5930-9905, Fox, Chris ORCID: https://orcid.org/0000-0001-9480-5704, Vauzour, David ORCID: https://orcid.org/0000-0001-5952-8756 and Minihane, Anne‐Marie ORCID: https://orcid.org/0000-0001-9042-4226 (2021) APOE4 genotype exacerbates the impact of menopause on cognition and synaptic plasticity in APOE‐TR mice. The FASEB Journal, 35 (5). ISSN 0892-6638

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The impact of sex and menopausal status in Alzheimer’s disease remains understudied despite increasing evidence of greater female risk, particularly in APOE4 carriers. Utilizing female APOE‐TR mice maintained on a high‐fat diet background we induced ovarian failure through repeated VCD injections, to mimic human menopause. At 12 months of age, recognition memory and spatial memory were assessed using object recognition, Y‐maze spontaneous alternation, and Barnes maze. A VCD*genotype interaction reduced the recognition memory (P < .05), with APOE4 VCD‐treated animals unable to distinguish between novel and familiar objects. APOE4 mice displayed an additional 37% and 12% reduction in Barnes (P < .01) and Y‐maze (P < .01) performance, indicative of genotype‐specific spatial memory impairment. Molecular analysis indicated both VCD and genotype‐related deficits in synaptic plasticity with BDNF, Akt, mTOR, and ERK signaling compromised. Subsequent reductions in the transcription factors Creb1 and Atf4 were also evident. Furthermore, the VCD*genotype interaction specifically diminished Ephb2 expression, while Fos, and Cnr1 expression reduced as a consequence of APOE4 genotype. Brain DHA levels were 13% lower in VCD‐treated animals independent of genotype. Consistent with this, we detected alterations in the expression of the DHA transporters Acsl6 and Fatp4. Our results indicate that the combination of ovarian failure and APOE4 leads to an exacerbation of cognitive and neurological deficits.

Item Type: Article
Uncontrolled Keywords: sdg 3 - good health and well-being ,/dk/atira/pure/sustainabledevelopmentgoals/good_health_and_well_being
Faculty \ School: Faculty of Medicine and Health Sciences > Norwich Medical School
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Depositing User: LivePure Connector
Date Deposited: 26 Apr 2021 23:47
Last Modified: 23 Oct 2022 02:24
URI: https://ueaeprints.uea.ac.uk/id/eprint/79880
DOI: 10.1096/fj.202002705R

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