Myelin lipid metabolism in brain ageing and carriers of dementia risk alleles

Abstract

Ageing is the greatest risk factor for Alzheimer’s disease (AD) and dementia overall. Apolipoprotein E (ApoE) is the major lipid transport protein in the brain, and inheritance of the e4 allele of the APOE gene (APOE4) is the most significant genetic risk factor for dementia. In contrast, APOE2 is protective, while the APOE3 allele is neutral for AD risk. The importance of lipid transport and homeostasis in the brain can be attributed largely to myelin, a lipid-rich membrane sheath that insulates neuronal axons. The dynamic turnover of myelin is necessary to maintain its integrity and requires the transport of lipid-rich cargo from degraded myelin for clearance. The work presented in this thesis aimed to determine how dementia risk variants in genes encoding the lipid handling proteins ApoE and TMEM106B alter lipid metabolism and myelin homeostasis to cause increased susceptibility to dementia with age.

TMEM106B risk allele (rs1990622) was associated with lower levels of myelin-enriched sphingolipids in the ageing human hippocampus, whereas APOE4 carriers showed a modest accumulation of myelin lipids. Lipidomic analyses of mice in which the murine Apoe locus has been replaced with the human variants (hAPOE2/2, hAPOE3/3, hAPOE4/4) showed that hAPOE4/4 mice have significantly higher levels of the myelin-enriched galactolipids hexosylceramides and sulfatides relative to hAPOE3/3 and hAPOE2/2 mice. More pronounced accumulation of these lipids was observed in the hippocampus of Apoe knockout (Apoe-/-) mice. We then developed and applied a stable isotope labelling method involving administration of deuterium oxide in the drinking water to measure turnover and synthesis of brain lipids in vivo, and established that the rate of myelin lipid turnover is reduced in Apoe-/- mice. These findings indicate that TMEM106B and APOE play key roles in the regulation of myelin lipid levels, and in the case of APOE, myelin lipid turnover.