Abstract

Brain cholesterol homeostasis is believed critical to brain function. Excess brain cholesterol can be enzymatically converted into cholesterol esters (CEs) by ACAT1 for intracellular storage as lipid droplets, and CE accumulation has been linked to age-related neurodegenerative diseases. 70-90% of brain cholesterol resides in myelin, which is supplied by oligodendrocytes (OLs) in the brain. Cholesterol is thought able to drive myelination and provide stability for myelin sheaths. Our preliminary data indicate that ACAT1 is expressed in both OL precursor cells (OPCs) and OLs in mice. Interestingly, we also found that ACAT1 expression and the levels of certain molecular species of CEs are markedly increased in old age in mouse brain white matter tissues that are rich in myelin. We hypothesize that CE accumulation in OLs may occur in ageing, impacting on OL function, myelin integrity and consequently on brain function. Currently little is known about the role of CEs in OLs. In this proposed study, we will purify myelin for lipidomics analysis to reveal how myelin CE levels change with age. We will also find out the role of CEs in OL development. Moreover, we will explore if CEs play a role in myelin maintenance in ageing as well as in age-related decline in OPCs’ ability to proliferate and differentiate into OLs. We plan to block CE production specifically in OL lineage cells, OPCs or OLs by breeding Acat1 conditional knockout mice (Acat1fl/fl) to OL lineage specific Cre, OPC- or OL-specific inducible Cre mice; in the brain of the progeny, we will examine the effect of lacking CEs on OPC proliferation/ differentiation, OL generation, OL morphology and myelin structure during OL development and in ageing with histological methods. In addition, we will feed ageing mice on a high cholesterol diet and evaluate the impact on myelin cholesterol/CE levels, OPCs, OLs and myelin structure in the ageing brain.