Altered cholesterol homeostasis in the ageing central nervous system: investigating a contributor to age-related CNS decline and dementia

Ageing of the central nervous system (CNS) is linked to cognitive impairment and the less frequent, but more debilitating, dementia, which are together responsible for drastically reduced functional independence and quality of life in the ageing population. Despite increased research, mechanisms by which ageing impacts cognitive function and leaves us vulnerable to the onset of age-related CNS pathology remains largely unresolved. Recent studies suggest that cholesterol regulation in the CNS is likely involved, being observed to be altered during normal ageing and closely linked to age-related pathological conditions like Alzheimer’s disease. Precise regulation of CNS cholesterol is vital, being essential for function, but cytotoxic in excess. Whilst the dysregulation with age has been conclusively demonstrated, there are significant gaps in understanding how these changes are occurring across different CNS regions and cell types, and the potential for these changes to be mitigated. This thesis addresses these gaps by investigating cholesterol homeostasis in various CNS regions and cell types, and exploring potential effects of lifestyle and pharmaceutical interventions. Gene expression analyses and cholesterol quantification were conducted to observe these effects using CNS tissues from C57BL/6 mice throughout the adult lifespan. Findings reveal both global and region-specific changes in cholesterol homeostasis, suggesting that ageing affects cholesterol regulation in the CNS through common and region-specific mechanisms and importantly, that these same mechanisms have the potential to be modulated through the use of interventions that alter key hallmarks of ageing. The production of detailed cell-type specific expression profiles for the major CNS cell types offer insights into their contributions, with many of the findings suggesting a shift in the cholesterol homeostatic roles of various CNS cell types with age, likely impacting the precise regulation seen in the young system. Furthermore, the data reinforces the hypothesis that age-related changes in cholesterol homeostasis is having both structural and functional effects on the ageing CNS, including altered myelin cholesterol. This research highlights the distinct changes in cholesterol homeostasis across different CNS regions and cell types with ageing, emphasizing the need and potential for targeted interventions to modulate these changes, to preserve a high quality of life with age.