Characterization of Lipid Bioenergetic Markers in Alzheimer's Disease (AD) in Apolipoprotein E4 (APOE) and non-E4 Carriers.

Huguenard, Claire J. C. (2022). Characterization of Lipid Bioenergetic Markers in Alzheimer's Disease (AD) in Apolipoprotein E4 (APOE) and non-E4 Carriers. PhD thesis The Open University.

DOI: https://doi.org/10.21954/ou.ro.00014274

Abstract

Alzheimer’s disease (AD) is a progressive neurodegenerative disease of ageing with an estimated prevalence of 36 million worldwide. Individuals carrying one ε4 allele of the apolipoprotein E gene (APOE) are 6 times more likely to develop AD than ε3 homozygotes. Further, ε4 carriers have an abnormal increased reliance on fatty acid oxidation (FAO). The L-carnitine system consisting of L-carnitine and its esters (acylcarnitines) plays an important role in FAO. We therefore hypothesized that changes in blood and brain levels of L-carnitine, its metabolites (TMAO and GBB) as well as acylcarnitines would be indicative of dysfunctional FAO in ageing ε4 carriers influencing AD onset and progression. The L-carnitine system was evaluated in blood and brain in association with APOE in multiple cohorts of controls and patients over the continuum of AD. To investigate the influence of age and APOE on this system a mouse model of AD with human APOE was examined. In this model ex vivo cerebrovascular uptake of L-carnitine metabolites and fatty acids (FAs) were also investigated in relation to APOE. Additionally, a 1-week L-carnitine oral challenge was performed to evaluate the influence of APOE on L-carnitine metabolism. These data suggested that the L-carnitine pathway is dysregulated early on in AD, particularly among ε4 carriers. In the brain, changes in the L-carnitine system were related to AD pathology in an APOE-dependent manner. In mouse models APOE did not affect cerebrovascular uptake of L-carnitine metabolites and FAs or the metabolism of L-carnitine after oral challenge. However, acylcarnitines were differentially affected in different genotypes after cerebrovascular uptake of compounds and L-carnitine challenge suggesting altered in FAO flux in different APOE genotypes.

Understanding disturbances in the L-carnitine system with age, in relation to APOE genotypes, and their collective contributions to AD will help develop targeted prevention and therapeutic strategies.

Viewing alternatives

Download history

Metrics

Public Attention

Altmetrics from Altmetric

Number of Citations

Citations from Dimensions

Item Actions

Export

About

Recommendations