AUTHOR=den Hoedt Sandra , Crivelli Simone M. , Leijten Frank P. J. , Losen Mario , Stevens Jo A. A. , Mané-Damas Marina , de Vries Helga E. , Walter Jochen , Mirzaian Mina , Sijbrands Eric J. G. , Aerts Johannes M. F. G. , Verhoeven Adrie J. M. , Martinez-Martinez Pilar , Mulder Monique T. 

TITLE=Effects of Sex, Age, and Apolipoprotein E Genotype on Brain Ceramides and Sphingosine-1-Phosphate in Alzheimer’s Disease and Control Mice

JOURNAL=Frontiers in Aging Neuroscience

VOLUME=13

YEAR=2021

URL=https://www.frontiersin.org/journals/aging-neuroscience/articles/10.3389/fnagi.2021.765252

DOI=10.3389/fnagi.2021.765252

ISSN=1663-4365

ABSTRACT=<p>Apolipoprotein ε4 (<italic>APOE</italic>)4 is a strong risk factor for the development of Alzheimer’s disease (AD) and aberrant sphingolipid levels have been implicated in AD. We tested the hypothesis that the <italic>APOE4</italic> genotype affects brain sphingolipid levels in AD. Seven ceramides and sphingosine-1-phosphate (S1P) were quantified by LC-MSMS in hippocampus, cortex, cerebellum, and plasma of &lt;3 months and &gt;5 months old human <italic>APOE3</italic> and <italic>APOE4-</italic>targeted replacement mice with or without the familial AD (FAD) background of both sexes (145 animals). <italic>APOE4</italic> mice had higher Cer(d18:1/24:0) levels in the cortex (1.7-fold, <italic>p</italic> = 0.002) than <italic>APOE3</italic> mice. Mice with AD background showed higher levels of Cer(d18:1/24:1) in the cortex than mice without (1.4-fold, <italic>p</italic> = 0.003). S1P levels were higher in all three brain regions of older mice than of young mice (1.7-1.8-fold, all <italic>p</italic> ≤ 0.001). In female mice, S1P levels in hippocampus (<italic>r</italic> = −0.54 [−0.70, −0.35], <italic>p</italic> &lt; 0.001) and in cortex correlated with those in plasma (<italic>r</italic> = −0.53 [−0.71, −0.32], <italic>p</italic> &lt; 0.001). Ceramide levels were lower in the hippocampus (3.7–10.7-fold, all <italic>p</italic> &lt; 0.001), but higher in the cortex (2.3–12.8-fold, <italic>p</italic> &lt; 0.001) of female than male mice. In cerebellum and plasma, sex effects on individual ceramides depended on acyl chain length (9.5-fold lower to 11.5-fold higher, <italic>p</italic> ≤ 0.001). In conclusion, sex is a stronger determinant of brain ceramide levels in mice than <italic>APOE</italic> genotype, AD background, or age. Whether these differences impact AD neuropathology in men and women remains to be investigated.</p>