Abstract
There is emerging evidence that amyloid beta (Aβ) aggregates forming neuritic plaques lead to impairment of the lipid-rich myelin sheath and glia. In this study, we examined focal myelin lipid alterations and the disruption of the myelin sheath associated with amyloid plaques in a widely used familial Alzheimer's disease (AD) mouse model; 5xFAD. This AD mouse model has Aβ42 peptide-rich plaque deposition in the brain parenchyma. Matrix-assisted laser desorption/ionization imaging mass spectrometry of coronal brain tissue sections revealed focal Aβ plaque-associated depletion of multiple myelin-associated lipid species including sulfatides, galactosylceramides, and specific plasmalogen phopshatidylethanolamines in the hippocampus, cortex, and on the edges of corpus callosum. Certain phosphatidylcholines abundant in myelin were also depleted in amyloid plaques on the edges of corpus callosum. Further, lysophosphatidylethanolamines and lysophosphatidylcholines, implicated in neuroinflammation, were found to accumulate in amyloid plaques. Double staining of the consecutive sections with fluoromyelin and amyloid-specific antibody revealed amyloid plaque-associated myelin sheath disruption on the edges of the corpus callosum which is specifically correlated with plaque-associated myelin lipid loss only in this region. Further, apolipoprotein E, which is implicated in depletion of sulfatides in AD brain, is deposited in all the Aβ plaques which suggest apolipoprotein E might mediate sulfatide depletion as a consequence of an immune response to Aβ deposition. This high-spatial resolution matrix-assisted laser desorption/ionization imaging mass spectrometry study in combination with (immuno) fluorescence staining of 5xFAD mouse brain provides new understanding of morphological, molecular and immune signatures of Aβ plaque pathology-associated myelin lipid loss and myelin degeneration in a brain region-specific manner. Read the Editorial Highlight for this article on page 7.
Highlights
According to the amyloid hypothesis, accumulation of amyloid beta (Aβ) plays a central and causative part in Alzheimer's disease (AD) pathogenesis and the rest of the disease process (Hardy & Higgins, 1992)
There was a focal loss of oligodendrocytes in sporadic and preclinical AD cases (Mitew et al, 2010) which is in line with the finding that amyloid-β peptides are cytotoxic to oligodendrocytes (Xu et al, 2001)
Lipidomics studies have revealed that galactosylceramide and their sulfated form, sulfatides, are the most typical lipids of myelin, where they are highly enriched and their abundance was found to be proportional to the amount of myelin present in the rat brain (Norton & Poduslo, 1973)
Summary
According to the amyloid hypothesis, accumulation of amyloid beta (Aβ) plays a central and causative part in Alzheimer's disease (AD) pathogenesis and the rest of the disease process (Hardy & Higgins, 1992). While recent data has revealed focal depletion of several sulfatide species in the amyloid plaques in the hippocampus and cerebral cortex of the brain in transgenic AD mice models, tgArcSwe (APPE693G(Arctic)/ KM670/671Nl(Swedish)) (Kaya, Brinet, Michno, Başkurt, et al, 2017; Kaya, Brinet, Michno, Syvänen, et al, 2017) and tgSwe (APP KM670/671Nl) (Michno et al, 2018), it still remains unknown whether these observations are associated with myelin disruption and/or other factors such as APOE in association with amyloid plaques in specific brain regions. High-spatial resolution MALDI-IMS of coronal brain tissue sections of 12-month-old 5xFAD mice revealed focal amyloid plaque-associated depletion of several myelin-associated lipid species. | 3 of myelin lipids which leverages the understanding of gray matter and white matter pathologies in AD
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