The interactive impact of omega-3 fatty acids, APOE genotype and sex hormones on cognition

Pontifex, Matthew (2020) The interactive impact of omega-3 fatty acids, APOE genotype and sex hormones on cognition. Doctoral thesis, University of East Anglia.

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Abstract

The impact of sex and menopause in Alzheimer’s disease remains understudied despite increasing evidence of greater female risk, particularly in middle aged APOE4 carriers. Exploratory analysis of data generated from the Cognitive Ageing Nutrition and Neurogenesis (CANN) study in humans revealed that APOE carrier-status and its interaction with hormone-therapy alter both circulating n-3 PUFA status and cognitive performance. Cognitive performance was greater in individuals receiving hormone-therapy, with specific APOE4 benefits apparent. To further study the influence of sex hormones on APOE4 status, we utilised a female APOE-TR mouse model, and induced ovarian failure (VCD injections). Recognition memory and spatial memory were assessed using object recognition, Y-maze, and Barnes maze. VCD abolished recognition memory in APOE4-TR mice (p<0.05), whilst APOE4 genotype alone led to ~45% and ~15% reductions in Barnes and Y-maze performance. Molecular analysis indicated both VCD and genotype related deficits in synaptic plasticity, which were more evident in APOE4-VCD treated animals, with Bdnf gene-expression and protein levels reduced 30% and 2-fold respectively. Brain DHA levels were 13% lower in VCD treated animals, independent of genotype. Model animals were provided with DHA-rich n-3 PUFA supplementation at two physiologically relevant doses to explore treatment efficacy. Deficits in recognition memory observed in APOE4 VCD treated mice were restored by high fish-oil supplementation (p < 0.05). Conversely, despite nominally increasing Barnes maze performance, high fish-oil supplementation did not significantly improve spatial memory impairment. Protein and gene-expression analysis again supported the behavioural findings with BDNF/Akt pathway significantly increased in response to high fish-oil in APOE4 mice (p < 0.05). High fish-oil also increased Igf-1, Mapk1 and Ntrk2 expression, potentially explaining BDNF/Akt modulation. Both doses were effective in restoring Brain DHA levels, however the higher dose increased DHA:AA further. Together, these results indicate cognitive and neurological impacts of menopause, which are exacerbated by APOE4, and ameliorated through high fish-oil supplementation.

Item Type:	Thesis (Doctoral)
Faculty \ School:	Faculty of Medicine and Health Sciences > Norwich Medical School
Depositing User:	Chris White
Date Deposited:	20 Jul 2020 08:15
Last Modified:	20 Jul 2020 08:15
URI:	https://ueaeprints.uea.ac.uk/id/eprint/76179
DOI:

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