i(3)so3-galactosylceramide and Alzheimer-Disease

Alzheimer's disease (AD) is the most common cause of dementia in the aging population. Prior work has shown that the epsilon4 allele of apolipoprotein E (apoE4) is a major risk factor for "sporadic" AD, which accounts for >99% of AD cases without a defined underlying mechanism. Recently, we have demonstrated that sulfatides are substantially and specifically depleted at the very early stage of AD. To identify the mechanism(s) of sulfatide loss concurrent with AD onset, we have found that: (1) sulfatides are specifically associated with apoE-associated particles in cerebrospinal fluid (CSF); (2) apoE modulates cellular sulfatide levels; and (3) the modulation of sulfatide content is apoE isoform dependent. These findings not only lead to identification of the potential mechanisms underlying sulfatide depletion at the earliest stages of AD but also serve as mechanistic links to explain the genetic association of apoE4 with AD. Moreover, our recent studies further demonstrated that (1) apoE mediates sulfatide depletion in amyloid-beta precursor protein transgenic mice; (2) sulfatides enhance amyloid beta (Abeta) peptides binding to apoE-associated particles; (3) Abeta42 content notably correlates with sulfatide content in CSF; (4) sulfatides markedly enhance the uptake of Abeta peptides; and (5) abnormal sulfatide-facilitated Abeta uptake results in the accumulation of Abeta in lysosomes. Collectively, our studies clearly provide a link between apoE, Abeta, and sulfatides in AD and establish a foundation for the development of effective therapeutic interventions for AD.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Animals, Genetically Modified; Apolipoproteins E; Humans; Molecular Structure; Peptide Fragments; Protein Isoforms; Sulfoglycosphingolipids

Multi-dimensional mass spectrometry-based shotgun lipidomics (MDMS-SL) is a well-developed technology for global lipid analysis, which identifies and quantifies individual lipid molecular species directly from lipid extracts of biological samples. By using this technology, we have revealed three marked changes of lipids in brain samples of subjects with mild cognitive impairment of Alzheimer's disease including sulfatides, ceramides, and plasmalogens. Further studies using MDMS-SL lead us to the identification of the potential biochemical mechanisms responsible for the altered lipids at the disease state, which are thoroughly discussed in this minireview. Specifically, in studies to identify the causes responsible for sulfatide depletion at the mild cognitive impairment stage of Alzheimer's disease, we have found that apolipoprotein E is associated with sulfatide transport and mediates sulfatide homeostasis in the nervous system through lipoprotein metabolism pathways and that alterations in apolipoprotein E-mediated sulfatide trafficking can lead to sulfatide depletion in the brain. Collectively, the results obtained from lipidomic analyses of brain samples provide important insights into the biochemical mechanisms underlying the pathogenesis of Alzheimer's disease.

Topics: Alzheimer Disease; Animals; Brain Chemistry; Cognition; Humans; Lipid Metabolism; Lipids; Mass Spectrometry; Models, Biological; Sulfoglycosphingolipids

Shotgun lipidomics is a rapidly developing technology, which identifies and quantifies individual lipid molecular species directly from lipid extracts of biological samples. Alterations in lipid molecular species in the brain induced by neurodegenerative diseases, such as Alzheimer's disease (AD) could provide fundamental clues to disease pathogenesis. To date, the cause(s) leading to AD pathogenesis are still unknown and apolipoprotein E (apoE) allele 4 is the only known major risk factor for this devastating disease. By utilizing shotgun lipidomics, we have recently shown that a substantial and specific depletion of sulfatide (a class of specialized myelin sphingolipids) is present in postmortem brains from subjects at the earliest clinically recognizable stage of AD. In subsequent studies to identify the biochemical mechanisms underlying sulfatide depletion at this very mild stage of AD, we have found that apoE is associated with sulfatide transport and mediates sulfatide homeostasis in the nervous system through lipoprotein metabolism pathways and that alterations in apoE-mediated sulfatide trafficking can lead to sulfatide depletion in the brain. Thus, a working model related to the potential biochemical mechanisms underlying sulfatide depletion in AD can be derived based on these results. Collectively, the results obtained from lipidomic analyses of brain samples provide important insights into the biochemical mechanisms underlying AD pathogenesis.

Topics: Alzheimer Disease; Animals; Humans; Lipid Metabolism; Sulfoglycosphingolipids

Lipids have many important yet distinct functions in cellular homeostasis such as forming an impermeable barrier separating intracellular and extracellular compartments, providing a matrix for the appropriate interactions of membrane-associated proteins, and serving as storage reservoirs for biologically active second messengers. Alterations in cellular lipids may therefore result in abnormal cellular functions. This review summarizes the results from the examination of lipid alterations in Alzheimer's disease (AD). In addition to the effects of cholesterol on AD, substantial depletions of plasmalogen and sulfatide as well as dramatic increases in ceramide are specifically manifested at the earliest clinically recognizable stage of AD. The potential mechanism(s) underlying these changes and the potential consequences of these changes in neuronal function and in AD development are also discussed. Collectively, this review will provide an overview of the lipid alterations in Alzheimer's disease and the relationship of these lipid alterations with the development of AD pathogenesis.

Topics: Alzheimer Disease; Apolipoproteins E; Ceramides; Cholesterol; Humans; Plasmalogens; Sulfoglycosphingolipids

Aging and neurodegenerative disease are accompanied by lipid perturbations in the brain. Understanding the changes in the contents and functional activity of lipids remains a challenge not only because of the many areas in which lipids perform bioactivities but also because of the technical limitations in identifying lipids and their metabolites. In the present study, we aimed to evaluate how brain lipids are altered in Alzheimer's disease (AD)-like pathology by using mass spectrometry imaging (MSI). The spatial distributions and relative abundances of lipids in the brains were compared between APP/PS1 mice and their age-matched wild-type (WT) mice by matrix-assisted laser desorption ionization (MALDI) MSI assays. The comparisons were correlated with the analysis using a spectrophotometric method to determine the relative contents of sulfatides in different brain regions. Significant changes of brain lipids between APP/PS1 and WT mice were identified: eight sulfoglycosphingolipid species, namely, sulfatides/sulfated hexosyl ceramides (ShexCer) and two glycerophosphoinositol (GroPIn) species, PI 36:4 and PI 38:4. The declines in the spatial distributions of these ShexCer and GroPIn species in the APP/PS1 mice brains were associated with learning- and memory-related brain regions. Compared with young WT mice, aged WT mice showed significant decreases in the levels of these ShexCer and GroPIn species. Our results provide technical clues for assessing the impact of brain lipid metabolism on the senescent and neurodegenerative brain. The decline in sulfatides and GroPIns may be crucial markers during brain senescence and AD pathology. Appropriate lipid complementation might be important potentials as a therapeutic strategy for AD.

Topics: Alzheimer Disease; Animals; Brain; Ceramides; Cognition; Disease Models, Animal; Mice; Neurodegenerative Diseases; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Sulfates; Sulfoglycosphingolipids

Gangliosides (GAs) and sulfatides (STs) are acidic glycosphingolipids that are particularly abundant in the nervous system and are closely related to aging and neurodegenerative disorders. To explore their roles in brain diseases, in-depth molecular profiling, including structural variations of sphingoid backbone, fatty acyl group, and sugar chain of GAs and STs was performed. A total of 210 GAs and 38 STs were characterized in the inferior frontal gyrus (IFG) of human brain, with 90 GAs discovered in brain tissues for the first time. Influential MS parameters for detecting GAs and STs in multiple reaction monitoring (MRM) mode were systematically examined and optimized to minimize in-source fragmentation, resulting in remarkable signal intensity enhancement for GAs and STs, especially for polysialylated species. To eliminate analytical variations, isotopic interference-free internal standards were prepared by simple and fast reduction reaction. The final established method facilitated the simultaneous quantitation of 184 GAs and 30 STs from 25 subtypes, which represents the highest number of GAs quantitated among all quantitation methods recorded in literature so far. The method was further validated and applied to reveal the aberrant change of GAs and STs in the IFG of 12 Alzheimer's disease (AD) patients. Four GAs exhibited high classification capacity for AD (AUC ≥0.80) and were thereby considered the most promising signatures for AD. These findings suggested the close correlation between GAs and the pathogenesis of AD, highlighting the achievements of our robust method for investigating the roles of GAs and STs in various physiological states and diseases.

Topics: Alzheimer Disease; Brain; Chromatography, High Pressure Liquid; Gangliosides; Humans; Sulfoglycosphingolipids

Despite being a brain disorder, Alzheimer's disease (AD) is often accompanied by peripheral organ dysregulations (e.g., loss of bladder control in late-stage AD), which highly rely on spinal cord coordination. However, the causal factor(s) for peripheral organ dysregulation in AD remain elusive.. The central nervous system (CNS) is enriched in lipids. We applied quantitative shotgun lipidomics to determine lipid profiles of human AD spinal cord tissues. Additionally, a CNS sulfatide (ST)-deficient mouse model was used to study the lipidome, transcriptome and peripheral organ phenotypes of ST loss.. We observed marked myelin lipid reduction in the spinal cord of AD subjects versus cognitively normal individuals. Among which, levels of ST, a myelin-enriched lipid class, were strongly and negatively associated with the severity of AD. A CNS myelin-specific ST-deficient mouse model was used to further identify the causes and consequences of spinal cord lipidome changes. Interestingly, ST deficiency led to spinal cord lipidome and transcriptome profiles highly resembling those observed in AD, characterized by decline of multiple myelin-enriched lipid classes and enhanced inflammatory responses, respectively. These changes significantly disrupted spinal cord function and led to substantial enlargement of urinary bladder in ST-deficient mice.. Our study identified CNS ST deficiency as a causal factor for AD-like lipid dysregulation, inflammation response and ultimately the development of bladder disorders. Targeting to maintain ST levels may serve as a promising strategy for the prevention and treatment of AD-related peripheral disorders.

Topics: Alzheimer Disease; Animals; Humans; Mice; Myelin Sheath; Spinal Cord; Sulfoglycosphingolipids; Urinary Bladder

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.

Topics: Alzheimer Disease; Animals; Brain; Humans; Lipidomics; Mice; Neurodegenerative Diseases; Sulfoglycosphingolipids

Sulfatides (STs) in cerebrospinal fluid (CSF), as well as magnetic resonance imaging (MRI)-detected white matter hyperintensities (WMHs), may reflect demyelination. Here, we investigated the diagnostic utility of CSF ST levels in the subcortical small vessel type of dementia (SSVD), which is characterized by the presence of brain WMHs.. To study the diagnostic utility of CSF ST levels in SSVD.. This was a mono-center, cross-sectional study of SSVD (n = 16), Alzheimer's disease (n = 40), mixed dementia (n = 27), and healthy controls (n = 33). Totally, 20 ST species were measured in CSF by liquid chromatography-mass spectrometry (LC-MS/MS).. CSF total ST levels, as well as CSF levels of hydroxylated and nonhydroxylated ST species, did not differ across the study groups. In contrast, CSF neurofilament light chain (NFL) levels separated the patient groups from the controls. CSF total ST level correlated with CSF/serum albumin ratio in the total study population (r = 0.64, p < 0.001) and in all individual study groups. Furthermore, CSF total ST level correlated positively with MRI-estimated WMH volume in the total study population (r = 0.30, p < 0.05), but it did not correlate with CSF NFL level.. Although there was some relation between CSF total ST level and WMH volume, CSF ST levels were unaltered in all dementia groups compared to the controls. This suggests that CSF total ST level is a poor biomarker of demyelination in SSVD. Further studies are needed to investigate the mechanisms underlying the marked correlation between CSF total ST level and CSF/serum albumin ratio.

Topics: Aged; Alzheimer Disease; Chromatography, Liquid; Cross-Sectional Studies; Dementia, Vascular; Demyelinating Diseases; Diagnosis, Differential; Diagnostic Techniques, Neurological; Female; Humans; Magnetic Resonance Imaging; Male; Neurofilament Proteins; Procedures and Techniques Utilization; Reproducibility of Results; Sulfoglycosphingolipids; White Matter

Alzheimer's disease (AD) is a progressive neurodegenerative disease affecting millions of patients worldwide. Previous studies have demonstrated alterations in the lipid composition of lipid extracts from plasma and brain samples of AD patients. However, there is no consensus regarding the qualitative and quantitative changes of lipids in brains from AD patients. In addition, the recent developments in imaging mass spectrometry methods are leading to a new stage in the in situ analysis of lipid species in brain tissue slices from human postmortem samples. The present study uses the matrix-assisted laser desorption/ionization imaging mass spectrometry (MALDI-IMS), permitting the direct anatomical analysis of lipids in postmortem brain sections from AD patients, which are compared with the intensity of the lipid signal in samples from matched subjects with no neurological diseases. The frontal cortex samples from AD patients were classified in three groups based on Braak's histochemical criteria, ranging from non-cognitively impaired patients to those severely affected. The main results indicate a depletion of different sulfatide lipid species from the earliest stages of the disease in both white and gray matter areas of the frontal cortex. Therefore, the decrease in sulfatides in cortical areas could be considered as a marker of the disease, but may also indicate neurochemical modifications related to the pathogenesis of the disease. This article is part of a Special Issue entitled: Membrane Lipid Therapy: Drugs Targeting Biomembranes edited by Pablo V. Escribá.

Topics: Alzheimer Disease; Frontal Lobe; Humans; Lipids; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Sulfoglycosphingolipids

To explore the hypothesis that alterations in cellular membrane lipids are present at the stage of pre-clinical Alzheimer's disease (AD) (i.e., cognitively normal at death, but with AD neuropathology), we performed targeted shotgun lipidomics of lipid extracts from post-mortem brains of subjects with pre-clinical AD. We found sulfatide levels were significantly lower in subjects with pre-clinical AD compared to those without AD neuropathology. We also found that the level of ethanolamine glycerophospholipid was marginally lower at this stage of AD, whereas changes of the ceramide levels were undetectable with the available samples. These results indicate that cellular membrane defects are present at the earliest stages of AD pathogenesis and also suggest that sulfatide loss is among the earliest events of AD development, while alterations in the levels of ethanolamine glycerophospholipid and ceramide occur relatively later in disease.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Brain; Ceramides; Female; Humans; Male; Plasmalogens; Sulfoglycosphingolipids; Tissue Extracts

Demyelination and axonal degeneration are the hallmarks of established white matter lesions (WML). The neurochemistry of ongoing WML is only partially known. We explored cerebrospinal fluid (CSF) substances as markers of brain tissue damage in relation to progression of WML rated on magnetic resonance imaging.. CSF from elderly individuals with WML was analyzed for amyloid markers, total τ, hyperphosphorylated τ, neurofilament protein light subunit, sulfatide and CSF/serum-albumin ratio. After 3 years, a follow-up magnetic resonance imaging was performed. Progression of WML was rated using the Rotterdam Progression Scale (RPS).. 37 subjects (age 73.6 ± 4.6 years) were included. Subjects with more pronounced progression (RPS > 2; n = 15) had lower mean sulfatide concentration at baseline as compared to subjects with no or minimal progression (RPS 0-2; n = 22) according to univariate analyses (p = 0.009). Sulfatide was the only biomarker that predicted the RPS score according to regression analysis, explaining 18.9% of the total variance (r = 0.38, p = 0.015).. The correlation of CSF sulfatide levels and RPS scores may reflect a remyelination response to the demyelination process associated with WML. Furthermore, the results strengthen the notion that WML pathology is different from that of Alzheimer's disease.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Biomarkers; Brain; Dementia, Vascular; Demyelinating Diseases; Disease Progression; Female; Humans; Image Processing, Computer-Assisted; Leukoaraiosis; Linear Models; Magnetic Resonance Imaging; Male; Nerve Degeneration; Netherlands; Neuropsychological Tests; Predictive Value of Tests; Socioeconomic Factors; Sulfoglycosphingolipids; tau Proteins

Sulfatide (ST) is a sphingolipid with an important role in the central nervous system as a major component of the myelin sheath. ST contains a structurally variable ceramide moiety, with a fatty acid substituent of varying carbon-chain length and double-bond number. Hydroxylation at the α-2 carbon position of the fatty acid is found in half the population of ST molecules. Recent genetic studies of fatty acid 2-hydroxylase (FA2H) indicate that these hydroxylated sphingolipids influence myelin sheath stability. However, their distribution is unknown. Matrix-assisted laser desorption/ionization imaging mass spectrometry (MALDI-IMS) enables the analysis of distinct distributions of individual ST molecular species in tissue section. We examined human cerebral cortex tissue sections with MALDI-IMS, identifying and characterizing the distributions of 14 ST species. The distribution analysis reveals that the composition ratios of non-hydroxylated/hydroxylated STs are clearly reversed at the border between white and gray matter; the hydroxylated group is the dominant ST species in the gray matter. These results suggest that hydroxylated STs are highly expressed in oligodendrocytes in gray matter and might form stable myelin sheaths. As a clinical application, we analyzed a brain with Alzheimer's disease (AD) as a representative neurodegenerative disease. Although previous studies of AD pathology have reported that the amount of total ST is decreased in the cerebral cortex, as far as the compositional distributions of STs are concerned, AD brains were similar to those in control brains. In conclusion, we suggest that MALDI-IMS is a useful tool for analysis of the distributions of various STs and this application might provide novel insight in the clinical study of demyelinating diseases.

Topics: Aged, 80 and over; Alzheimer Disease; Amidohydrolases; Brain Mapping; Cerebral Cortex; Female; Humans; Male; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Sulfoglycosphingolipids; Tandem Mass Spectrometry; Tissue Distribution

Herein, we tested a recently proposed working model of apolipoprotein E (apoE)-mediated sulfatide metabolism/trafficking/homeostasis with two well-characterized amyloid precursor protein (APP) transgenic (Tg) animal models of Alzheimer's disease (AD) (i.e., APP(V717F) and APPsw) on a wild-type murine apoE background or after being bred onto an Apoe(-/-) background. As anticipated, lipidomics analysis demonstrated that the sulfatide levels in brain tissues were reduced beginning at approximately 6 months of age in APP(V717F) Tg, Apoe(+/+) mice and at 9 months of age in APPsw Tg, Apoe(+/+) mice relative to their respective non-APP Tg littermates. This reduction increased in both APP Tg mice as they aged. In contrast, sulfatide depletion did not occur in APP Tg, Apoe(-/-) animals relative to the Apoe(-/-) littermates. The lack of sulfatide depletion in APP Tg, Apoe(-/-) mice strongly supports the role of apoE in the deficient sulfatide content in APP Tg, Apoe(+/+) mice. Collectively, through different animal models of AD, this study provides evidence for an identified biochemical mechanism that may be responsible for the sulfatide depletion at the earliest stages of AD.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Apolipoproteins E; Brain; Brain Chemistry; Disease Models, Animal; Down-Regulation; Homeostasis; Lipid Metabolism; Lipoproteins; Mice; Mice, Knockout; Mice, Transgenic; Models, Biological; Myelin Sheath; Sphingomyelins; Sulfoglycosphingolipids

Altered sphingolipid metabolism plays an emergent role in the etiology of Alzheimer's disease (AD). In this study, we determined the levels of ceramides and other related-sphingolipids (sphingomyelins, sulfatides and galactosylceramides) in the cerebral cortex of an APP(SL)/PS1Ki mouse model of AD. The results demonstrate that ceramides accumulated in the cortex of APP(SL)/PS1Ki mice, but not in PS1Ki mice, whereas all others major sphingolipids (except galactosylceramides) were not altered in comparison with those from age-matched wild-type mice. Furthermore, as early as 3 months of age, female mice but not males, exhibit a strong increase in 2-hydroxy fatty acid-containing ceramides, whereas males display a significant elevation of non-hydroxy fatty acid ceramide species. Therefore, the gender differences in ceramide accumulation in the brain of mice expressing APP(SL) suggest that additional factors like modified ceramide metabolism may contribute to the increased propensity of females to develop AD.

Topics: Alzheimer Disease; Amyloid beta-Protein Precursor; Animals; Ceramides; Cerebral Cortex; Disease Models, Animal; Female; Galactosylceramides; Gene Knock-In Techniques; Male; Mice; Mice, Transgenic; Sex Factors; Sphingomyelins; Sulfoglycosphingolipids

Topics: Alzheimer Disease; Amyloid beta-Peptides; Apolipoproteins E; Biomarkers; Brain; Ceramides; Genotype; Humans; Phosphatidylinositols; Sensitivity and Specificity; Severity of Illness Index; Sulfoglycosphingolipids

We recently noted a profound decline in brain sulfatides (ST) in subjects who died with incipient dementia due to Alzheimer's disease. Herein, we measured ST levels in cerebrospinal fluid in cognitively normal elderly and in subjects with mild cognitive impairment due to incipient demenia of the Alzheimer type. There was a significant decrease in cerebrospinal fluid ST and in the ST to phosphatidylinositol ratio in MCI subjects. The ST to phosphatidylinositol ratio accurately differentiated very mildly impaired subjects from controls on an individual basis. The cerebrospinal fluid ST to phosphatidylinositol ratio may be a very useful biomarker for the earliest clinical stage of Alzheimer's disease.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Brain; Cognition Disorders; Female; Follow-Up Studies; Humans; Male; Middle Aged; Neuropsychological Tests; Phosphatidylinositols; Sensitivity and Specificity; Severity of Illness Index; Sulfoglycosphingolipids

Recently, we have demonstrated that sulfatide content was substantially depleted in post-mortem brain samples from subjects with very mild Alzheimer's disease (AD) relative to age-matched controls. However, it is unknown if the observed sulfatide deficiency is AD-specific and what mechanism(s) lead to this depletion. By exploiting the advantages of electrospray ionization mass spectrometry techniques, we examined the specificity and a potential mechanism of sulfatide deficiency in AD in the study. In contrast to the sulfatide depletion observed in AD, it was found that the sulfatide content in post-mortem brain samples from subjects with Parkinson's disease and dementia with Lewy bodies was either higher than or comparable to that observed from controls, respectively, suggesting that sulfatide deficiency is likely specific to AD. Examination of lipid alterations in cultured embryonic rat brain oligodendrocytes treated with amyloid-beta peptide demonstrated that there was no alteration in sulfatide content up to a 24-hr interval after amyloid-beta addition/treatment. However, there were significant decreases in plasmenylethanolamine and increases in sphingomyelin content in the same study. These findings suggest that sulfatide deficiency in AD is unlikely mediated directly by amyloid-beta peptide accumulation. Thus, these results illustrate the specificity of sulfatide deficiency in AD and exclude amyloid-beta accumulation as a factor directly contributing to sulfatide deficiency in AD.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Animals; Brain; Brain Chemistry; Cells, Cultured; Fatty Acids; Galactosylceramides; Humans; Lewy Body Disease; Lipids; Lithium Compounds; Oligodendroglia; Parkinson Disease; Peptide Fragments; Phosphatidylcholines; Phosphatidylethanolamines; Phosphatidylglycerols; Phosphatidylinositols; Phosphatidylserines; Plasmalogens; Rats; Spectrometry, Mass, Electrospray Ionization; Sphingomyelins; Sulfoglycosphingolipids

In addition to pathology in the gray matter, there are also abnormalities in the white matter in Alzheimer's disease (AD). Sulfatide species are a class of myelin-specific sphingolipids and are involved in certain diseases of the central nervous system. To assess whether sulfatide content in gray and white matter in human subjects is associated with both the presence of Alzheimer's disease (AD) pathology as well as the stage of dementia, we analyzed the sulfatide content of brain tissue lipid extracts by electrospray ionization mass spectrometry from 22 subjects whose cognitive status at time of death varied from no dementia to very severe dementia. All subjects with dementia had AD pathology. The results demonstrate that: (i) sulfatides were depleted up to 93% in gray matter and up to 58% in white matter from all examined brain regions from AD subjects with very mild dementia, whereas all other major classes of lipid (except plasmalogen) in these subjects were not altered in comparison to those from age-matched subjects with no dementia; (ii) there was no apparent deficiency in the biosynthesis of sulfatides in very mild AD subjects as characterized by the examination of galactocerebroside sulfotransferase activities in post-mortem brain tissues; (iii) the content of ceramides (a class of potential degradation products of sulfatides) was elevated more than three-fold in white matter and peaked at the stage of very mild dementia. The findings demonstrate that a marked decrease in sulfatides is associated with AD pathology even in subjects with very mild dementia and that these changes may be linked with early events in the pathological process of AD.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Brain; Brain Chemistry; Ceramides; Dementia; Disease Progression; Galactosylceramides; Humans; Neuropsychological Tests; Severity of Illness Index; Spectrometry, Mass, Electrospray Ionization; Sphingomyelins; Sulfoglycosphingolipids; Sulfotransferases

Brain tissue from 12 subjects with pure Alzheimer's disease (AD) and 21 subjects with senile dementia of the Alzheimer type (SDAT) was investigated for membrane lipids and compared with that in age-matched controls. In brain tissue from the patients with AD, phospholipids were significantly decreased compared with that from SDAT patients and controls, cholesterol was reduced compared with that in controls, and gangliosides were significantly reduced in all gray-matter areas investigated compared with those in both SDAT subjects and controls. A reduction in gangliosides also occurred in the SDAT group, but it was smaller. In the white matter, the pattern of changes was the opposite. Phospholipids, cholesterol, cerebroside, and sulfatide were significantly reduced in the frontal-lobe white matter in the SDAT group compared with that in age-matched controls and AD patients. Gangliosides in the cerebrospinal fluid also separated AD from SDAT and controls. The findings indicate synapse degeneration as an important pathogenetic factor in AD. This disorder should be separated from SDAT, in which white-matter degeneration appears to be more prominent.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Brain; Cerebrosides; Cholesterol; Female; Frontal Lobe; Gangliosides; Humans; Male; Membrane Lipids; Phospholipids; Reference Values; Sulfoglycosphingolipids; Synaptic Membranes

The myelin-associated glycosphingolipid sulfatide in cerebrospinal fluid (CSF) was investigated in 20 patients with vascular dementia (VAD), 43 with Alzheimer's disease (AD) and 20 age-matched controls. The sulfatide concentration in the VAD group (307 +/- 118 nmol/l) was significantly (p less than 0.0001) higher than that in controls (145 +/- 86 nmol/l) and the AD group (178 +/- 79 nmol/l). Among the VAD patients, 8/20 had a significantly increased concentration of sulfatide (greater than mean + 2 S.D.), as compared with controls, while only 2/43 of the AD patients had a sulfatide concentration above this level. It is suggested that the elevated concentration of sulfatide in CSF from VAD patients reflects demyelination. Furthermore, sulfatide determinations, when combined with clinical findings, may be of diagnostic value, for discriminating between VAD and AD.

Topics: Aged; Alzheimer Disease; Dementia, Vascular; Diagnosis, Differential; Female; Humans; Male; Mental Status Schedule; Middle Aged; Sulfoglycosphingolipids

Immunohistological and biochemical studies were initiated to determine whether or not neural membrane components were associated with degenerative changes characteristic of Alzheimer's disease (AD). Monoclonal antibody A2B5, developed against embryonic chick retinal cells and previously shown to react with neural surface gangliosides, was applied to formalin-fixed sections of control and AD brain tissue. Frontal cortex and hippocampus of AD cases exhibited high levels of A2B5 immunoreactivity within those neurons undergoing neurofibrillary degeneration. Neuritic processes associated with senile plaques were also highly reactive with the A2B5 antibody. The amount of gangliosides and their pattern after HPTLC were the same in control and AD cases. However, the unexpected observation was made that the A2B5 antibody reacted with human brain sulfatides in addition to the expected reactivity with minor gangliosides. The average level of sulfatides in AD brain was significantly higher than in normal controls. The data support the involvement of one or more membrane components with neurodegeneration in the Alzheimer brain.

Topics: Alzheimer Disease; Animals; Antibodies, Monoclonal; Antigens, Surface; Benzothiazoles; Brain Chemistry; Cell Membrane; Chick Embryo; Fluorescent Antibody Technique; Frontal Lobe; Gangliosides; Hippocampus; Histocytochemistry; Humans; Immunoenzyme Techniques; Mice; Neurofibrils; Retina; Sulfoglycosphingolipids; Thiazoles