Electrocorticographic and Astrocytic Signatures of Stearoyl-CoA Desaturase Inhibition in the Triple Transgenic Mouse Model of Alzheimer’s Disease

The symptomatology of Alzheimer’s disease (AD) includes cognitive deficits and sleep disturbances. Recent findings suggest the involvement of dysfunctions in lipid metabolism, such as oleic acid build-up, in the brain of AD patients and animal models. In addition, the inhibition of stearoyl-CoA desaturase (SCD), a lipid-converting enzyme, was shown to restore memory in triple transgenic (3xTg)-AD mice. In the brain, astrocytes regulate the synthesis of specific lipids. Alterations in astrocytes and their function were reported in AD patients and animal models, and astrocytes have been implicated in the regulation of sleep. However, the relationship between sleep disturbances, astrocytes and lipid metabolism remains to be explored in AD. This project thus aimed at assessing whether the inhibition of SCD restores sleep in 3xTg-AD mice, and whether this associated with modifications in astrocytic function. Wild-type (WT) and 3xTg-AD female mice (4-months old) received intracerebroventricular infusion of a SCD inhibitor (SCDi) or vehicle for 28 days, and a 24-hour electrocorticographic (ECoG) recording was conducted post-treatment. Post-mortem brain slices were stained for the astrocytic markers glial fibrillary acidic protein (GFAP) and 10-formyltetrahydrofolate dehydrogenase (ALDH1L1) to perform cell counting and/or morphological evaluation in the hippocampus, lateral hypothalamus and thalamus. The results indicate that the reduced time spent awake and increased time spent in slow wave sleep (SWS) in 3xTg-AD mice was not restored by the SCDi treatment. Similar observations were made concerning the increased number of wake and SWS bouts in 3xTg-AD mice. Rhythmic and scale-free ECoG activity were markedly altered in 3xTg-AD mice for all wake/sleep states, and SCDi significantly altered these phenotypes in a different manner in mutant mice in comparison to WT mice. GFAP- and ALDH1L1-positive cell densities were elevated in the hippocampus and lateral hypothalamus/thalamus of 3x-Tg-AD mice, respectively, and SCDi rescued the increase in the CA1 region in particular. Overall, these findings suggest that the multiple wake/sleep alterations in 3xTg-AD mice are not substantially restored by targeting lipid metabolism using SCD inhibition, at least for the targeted age window, but that this treatment can revert hippocampal changes in astrocytes. This work will benefit the understanding of the pathophysiology related to AD and associated sleep disturbances. ### Competing Interest Statement The authors have declared no competing interest. * 3xTg : triple transgenic aCSF : artificial cerebrospinal fluid AD : Alzheimer’s disease ALDH1L1 : aldehyde dehydrogenase 1 family member L1 or 10-formyltetrahydrofolate dehydrogenase ANOVA : analysis of variance DAPI : 4′,6-diamidino-2-phenylindole DG : dentate gyrus DMSO : dimethylsulfoxide ECoG : electrocorticographic EMG : electromyographic GFAP : glial fibrillary acidic protein IHC : immunohistochemistry LH : lateral hypothalamus PBS : phosphate-buffered saline PS : paradoxical sleep SCD : stearoyl-CoA desaturase SCDi : stearoyl-CoA desaturase inhibitor SEM : standard error of the mean SWA : slow wave activity SWS : slow wave sleep WT : wild-type.