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. 2022 Dec 23;24(1):233.
doi: 10.3390/ijms24010233.

Sulfatide Deficiency, an Early Alzheimer's Lipidomic Signature, Causes Brain Ventricular Enlargement in the Absence of Classical Neuropathological Hallmarks

Juan Pablo Palavicini  1   2 , Lin Ding  1   3 , Meixia Pan  1 , Shulan Qiu  1 , Hu Wang  1 , Qiang Shen  4   5 , Jeffrey L Dupree  6   7 , Xianlin Han  1   2
Affiliations

Sulfatide Deficiency, an Early Alzheimer's Lipidomic Signature, Causes Brain Ventricular Enlargement in the Absence of Classical Neuropathological Hallmarks

Juan Pablo Palavicini et al. Int J Mol Sci. .

Abstract

Alzheimer's disease (AD) is a neurodegenerative disease characterized by progressive memory loss and a decline in activities of daily life. Ventricular enlargement has been associated with worse performance on global cognitive tests and AD. Our previous studies demonstrated that brain sulfatides, myelin-enriched lipids, are dramatically reduced in subjects at the earliest clinically recognizable AD stages via an apolipoprotein E (APOE)-dependent and isoform-specific process. Herein, we provided pre-clinical evidence that sulfatide deficiency is causally associated with brain ventricular enlargement. Specifically, taking advantage of genetic mouse models of global and adult-onset sulfatide deficiency, we demonstrated that sulfatide losses cause ventricular enlargement without significantly affecting hippocampal or whole brain volumes using histological and magnetic resonance imaging approaches. Mild decreases in sulfatide content and mild increases in ventricular areas were also observed in human APOE4 compared to APOE2 knock-in mice. Finally, we provided Western blot and immunofluorescence evidence that aquaporin-4, the most prevalent aquaporin channel in the central nervous system (CNS) that provides fast water transportation and regulates cerebrospinal fluid in the ventricles, is significantly increased under sulfatide-deficient conditions, while other major brain aquaporins (e.g., aquaporin-1) are not altered. In short, we unraveled a novel and causal association between sulfatide deficiency and ventricular enlargement. Finally, we propose putative mechanisms by which sulfatide deficiency may induce ventricular enlargement.

Keywords: Alzheimer’s disease; aquaporins; brain MRI; cerebroside sulfotransferase; sulfatide; ventricular enlargement.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Mild sulfatide deficiency leads to middle-age ventricular enlargement in the mammalian brain. (A) Total sulfatide levels in the cerebrum of CST+/+ and CST+/− littermate mice measured by MDMS-SL. (B) DAPI- (nuclear) stained coronal sections from CST+/+ and CST+/− mouse brains on a C57BL/6J background at 12 months of age. Scale bar: 1 mm. Lateral ventricle (C), hippocampal (D) and whole hemibrain (E) areas from CST+/+ and CST+/− mice. Anatomical areas were quantified using Image J. N = 4–5 mice/genotype. Each dot represents average data from 2–4 sections (Bregma −1.8 to −2) for each animal. Unpaired two-tailed t-test (normality and equal variance were assumed/confirmed). * p < 0.05, *** p < 0.001.
Figure 2
Figure 2
Enlarged brain ventricles in living sulfatide deficient mice. (A) Representative MRI images from CST+/+ and CST+/− mice. White areas represent water/CSF filled ventricles. Scale bar: 2 mm. Lateral ventricle (B), hippocampus (C), and whole brain (D) volumes were calculated by summing-up the area of each imaged section multiplied by slice thickness for each mouse brain. N = 5–7 mice/genotype. Unpaired two-tailed t-test (normality and equal variance were assumed/confirmed). * p < 0.05.
Figure 3
Figure 3
Adult-onset sulfatide deficiency leads to old age ventricular enlargement in the mammalian brain. (A) Representative DAPI-stained images of coronal brain sections from 15- and 20-month-old Cre+ and Cre− mice following tamoxifen induction at 3 months of age. Scale bar: 1 mm. (B) Total sulfatide in cerebrum samples from Cre+ and Cre− mice measured by MDMS-SL. Lateral ventricle (C), hippocampal (D), and whole hemibrain (E) areas from mouse brain sections. N = 3–5 mice/genotype. Each dot represents average data from 2–4 sections (Bregma −1.8 to −2) for each animal. Two-way ANOVA (Tukey) for (A,B) and unpaired two-tailed t-test for (D,E) (normality and equal variance were assumed/confirmed). ** p < 0.01, *** p < 0.001.
Figure 4
Figure 4
APOE isoform-dependent sulfatide deficiency and brain ventricular enlargement. (A) Total sulfatide levels in cerebrum samples from 9-month-old APOE KO, APOE2, APO3, APO4 knock-in (KI) mice were measured by MDMS-SL. (B) Individual sulfatide molecular species and total levels in APOE2 and APOE4 KI mouse brains. (C) Representative DAPI-stained images of coronal brain sections. Scale bar: 1 mm. Lateral ventricle (D), hippocampal (E), and whole brain (F) areas from mouse brain sections. N = 3–5 mice/genotype. Each dot represents an animal in (A) and a brain section (Bregma −1.8 to −2) in (D–F) (3–5 brain sections/animal). Ordinary one-way ANOVA (Tukey) for (A,E,F); multiple unpaired two-tailed t-test for (B); Welch ANOVA for (D). # p < 0.15, * p < 0.05, ** p < 0.01.
Figure 5
Figure 5
Aquaporin levels in the sulfatide deficient mouse brain. (A) Expression of AQP1 and AQP4 in Cre+ and Cre− cerebrum samples were measured by Western Blot and quantified (B,C). Multiple AQP4 bands with different levels of glycosylation were observed (bracket). (D) Representative immunofluorescence image for AQP4 (red) in the CST cKO mouse brain at 20 months of age. Scale bar: 250 μm. (E) AQP4 immunofluorescent area around the lateral ventricle was quantified using Image J. Unpaired two-tailed t-test (normality and equal variance were assumed/confirmed). ** p < 0.01.
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References

    1. Bateman R.J., Xiong C., Benzinger T.L., Fagan A.M., Goate A., Fox N.C., Marcus D.S., Cairns N.J., Xie X., Blazey T.M., et al. Clinical and biomarker changes in dominantly inherited Alzheimer’s disease. N. Engl. J. Med. 2012;367:795–804. doi: 10.1056/NEJMoa1202753. - DOI - PMC - PubMed
    1. Selkoe D.J., Hardy J. The amyloid hypothesis of Alzheimer’s disease at 25 years. EMBO Mol. Med. 2016;8:595–608. doi: 10.15252/emmm.201606210. - DOI - PMC - PubMed
    1. Villemagne V.L., Burnham S., Bourgeat P., Brown B., Ellis K.A., Salvado O., Szoeke C., Macaulay S.L., Martins R., Maruff P., et al. Amyloid beta deposition, neurodegeneration, and cognitive decline in sporadic Alzheimer’s disease: A prospective cohort study. Lancet Neurol. 2013;12:357–367. doi: 10.1016/S1474-4422(13)70044-9. - DOI - PubMed
    1. Carmichael O.T., Kuller L.H., Lopez O.L., Thompson P.M., Dutton R.A., Lu A., Lee S.E., Lee J.Y., Aizenstein H.J., Meltzer C.C., et al. Cerebral ventricular changes associated with transitions between normal cognitive function, mild cognitive impairment, and dementia. Alzheimer Dis. Assoc. Disord. 2007;21:14–24. doi: 10.1097/WAD.0b013e318032d2b1. - DOI - PMC - PubMed
    1. Luxenberg J.S., Haxby J.V., Creasey H., Sundaram M., Rapoport S.I. Rate of ventricular enlargement in dementia of the Alzheimer type correlates with rate of neuropsychological deterioration. Neurology. 1987;37:1135–1140. doi: 10.1212/WNL.37.7.1135. - DOI - PubMed

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