Brain lipids: Male mice show their age

Lipidomics Gateway (28 October 2009) [doi:10.1038/lipidmaps.2009.28]

Comparing brain phospholipid profiles in mice reveals substantial age-related differences in males, but not females, which may contribute to the etiology of Parkinson's disease.

© Rama, Cc-by-sa-2.0-fr

Healthy brains undergo significant changes during ageing, and some brain pathologies, such as Parkinson's disease, can also be age-related. Modern lipidomic techniques ¹ now allow for a much more detailed analysis of lipid profiles than previously possible, but data on brain lipid changes have so far been limited to broad lipid classes or specific sample types. α-Synuclein (αSyn) is thought to influence brain lipid composition and is implicated in fatty acid metabolism, regulation of membrane composition, and the release of synaptic vesicles. Early-onset Parkinson's disease can be caused by alterations at the genetic level, and αSyn is known to accumulate in the insoluble aggregates that define the illness; however, its precise function is not known. Now, in work partially funded by LIPID MAPS, Alex Brown and Dennis Selkoe's groups have analyzed the effect of αSyn gene dosage on brain phospholipid profiles in two mouse strains. Their report in the Journal of Neurochemistry reveals some αSyn-dependent differences in the profiles, but the most profound alterations were found to stem from ageing. Surprisingly, these differences are specific to males, and may help to explain why Parkinson's disease is more prevalent in men than women.

One of the key approaches underpinning the current revolution in lipidomics research is the use of electrospray ionization coupled with tandem mass spectrometry, often used alongside sample separation by liquid chromatography (ESI/LC/MS/MS). Brown and colleagues used this technique to analyze mouse brain phospholipid and lysophospholipid profiles in two mouse strains according to several parameters: age, gender, specific brain region, and αSyn gene dosage (transgenic overexpression, knockout or heterozygote). Internal standards for each glycerophospholipid class provided reference MS peak heights, against which the sample MS intensities were normalized. The authors employed ratios to analyze the level of each species as a proportion of its overall class, and each class as a proportion of overall phospholipids. With so many variables, the authors used principle components analysis to distinguish which parameters were associated with specific alterations in phospholipid profiles.

Surprisingly, the authors found that the greatest changes in profiles were age-related and mostly driven by differences in male mice only. For example, the overall levels of phosphatidic acid (PA) and lysophosphatidic acid (LPA) were much greater in aged male mice than young male mice, but were comparable in both age groups for females. Phosphatidylcholine (PC), on the other hand, was significantly reduced in older mice of both genders. Individual lipid species showed differential changes; for example, 18:1 and 20:1 lysophosphatidylcholine (LPC) levels increased with age, whereas 18:0 and 22:6 LPC both decreased.

The gene dosage of αSyn had little effect on phospholipid profiles in young mice, but some differences became apparent with age. There was a strong interaction between age and αSyn gene dosage on the levels of several lysophospholipid classes. Overexpression also eliminated much of the age-dependent variability seen in wild-type male mice.

Although this study revealed that αSyn gene dosage only had a limited effect on lipid profiles in comparison to that of age and gender, the latter two variables might have important implications for αSyn function. The impact of pathological changes in αSyn activity could be greater against the lipidomic backdrop of aged male brains, helping to explain why the incidence of Parkinson's disease is higher in men. Furthermore, the functions of numerous membrane-associated proteins are affected by their lipid microenvironment, suggesting that altered lipid profiles might participate in other age-related changes.

Emma Leah