A Comprehensive Characterization of the Phospholipid and Cholesterol Composition of the Uncinate Fasciculus in the Human Brain: Evidence of Age-Related Alterations

The uncinate fasciculus (UF) is a long-range association fiber tract connecting the anterior temporal lobe with the orbitofrontal cortex and has been linked to a multitude of physiological and pathophysiological conditions such as aging, epilepsy, and the vulnerability to psychopathology posed by a history of childhood abuse (CA). Since the myelin sheath is highly enriched in lipids, changes in white matter (WM) microstructure observed via neuroimaging may reflect alterations in the myelin lipid profile. Given that the UF does not exist in rodents, its molecular properties are highly understudied. Therefore, we sought to quantify the phospholipid FA and cholesterol quantities of the human postmortem UF and evaluate any lipid-related or myelin-constituent gene/protein changes associated with age and history of CA. UF samples were analyzed from individuals with depression who died by suicide with (DS-CA) or without (DS) severe CA, and control individuals (CTRL), with an age span of 15 to 85 years. Phospholipids were separated by thin-layer chromatography; FAs and nonderivatized cholesterol were quantified by gas chromatography-flame ionization detection. The relative expression of myelin-constituent genes and proteins was measured by RT-qPCR and immunoblotting, respectively. We found no robust relationships between CA or depression and lipid measures or myelin-constituent gene/protein levels. In contrast, phospholipids showed pronounced age effects that differed by fraction, with an overall trend of monounsaturated FAs increasing and long-chain omega-6 polyunsaturated FAs decreasing with age. The expression of most myelin-constituent genes and proteins declined with age; PLP1 and MAG showed significant decreases. Therefore, changes in lipid composition and lipid-protein interactions likely contribute to age-related myelin deficits and may in part underlie age-associated cognitive decline.