The regulation of brain-derived neurotrophic factor in cognitive ageing

Aarons, Toby (2018) The regulation of brain-derived neurotrophic factor in cognitive ageing. Masters by Research thesis (MSc), Manchester Metropolitan University.

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Abstract

Introduction: Brain-derived neurotrophic factor (BDNF) is essential for neurogenesis and synaptic plasticity, which are important in memory, particularly in neurons in the prefrontal cortex and hippocampus. Declining BDNF levels have been suggested to contribute to cognitive ageing, which in the context of a globally ageing population, needs to be investigated further, particularly in regards to underlying epigenetic regulation. Methods: We investigated BDNF and cognitive ageing in the MyoAge population, which consisted of cognitively healthy young (n=135, 23.4 ± 2.7 years) and older (n=226, 74.5 ± 3.4 years) adults. Cognitive function had previously been tested using CANTAB. Investigation of BDNF and Alzheimer’s disease was performed in the Dyne-Steele cohort (n=67). Bisulfite pyrosequencing was used to quantify BDNF methylation. Genotyping was performed on the BDNF Val66Met polymorphism. RT-PCR was used to quantify BDNF gene expression. Chromatin Immunoprecipitation and subsequent allele discrimination via pyrosequencing was used to determine gene-environment interactions. Results: In the MyoAge cohort, we observed that BDNF exon I methylation is associated with cognitive decline in the male population, with higher BDNF exon I methylation associated with worse executive functioning and working memory capacity in the old males (P=0.001, P=0.011, respectively). Physical activity was associated with reduced methylation of BDNF exon IV in the older females (P=0.033). Early life education is associated with reduced BDNF methylation in the older adults. In the Dyne-Steele cohort, BDNF exon I expression was associated with faster rates of memory decline in the AD group. BDNF exon I methylation was associated with BDNF gene expression in the healthy group, but not the AD group. Histone H3K27ac marker bound more readily to the BDNF rs56133711 A allele. Discussion: These results suggest that BDNF methylation is associated with cognitive decline in the older population. Lifestyle factors play a significant role in BDNF methylation and should be considered with further investigation of BDNF methylation and cognitive ageing. BDNF could act to compensate AD damage, however AD neuropathology appears to interfere with epigenetic regulation of BDNF.