dolichols and Alzheimer-Disease

This study assessed the changes in the isoprenoid pathway and the consequences of its dysfunction in Alzheimer's disease (AD). The isoprenoid pathway and digoxin status were also studied for comparison in individuals of differing hemispheric dominance to find the role of cerebral dominance in the genesis of Alzheimer's disease. There was elevation in plasma HMG CoA reductase activity, serum digoxin, and dolichol levels, and a reduction in serum magnesium, RBC membrane Na(+)-K+ ATPase activity, and serum ubiquinone levels. Serum tryptophan, serotonin, strychnine, nicotine, and quinolinic acid were elevated, while serum tyrosine, morphine, dopamine, and noradrenaline were decreased. The total serum glycosaminoglycans and glycosaminoglycan fractions, the activity of GAG degrading enzymes and glycohydrolases, carbohydrate residues of glycoproteins, and serum glycolipids were elevated in Alzheimer's disease. HDL cholesterol was reduced and free fatty acids increased. The RBC membrane glycosaminoglycans, hexose, and fucose residues of glycoproteins and cholesterol were reduced, while phospholipid increased. The activity of all free radical scavenging enzymes, concentration of glutathione, alpha tocopherol, iron binding capacity, and ceruloplasmin decreased significantly in Alzheimer's disease, while the concentration of lipid peroxidation products and NO increased. The hypomagnesemia-related NMDA excitotoxicity, ubiquinone deficiency related mitochondrial dysfunction, and altered glycoconjugates/lysosomal stability could contribute to the pathogenesis of Alzheimer's disease. The biochemical patterns, including hyperdigoxinemia observed in Alzheimer's disease, correlated with those obtained in right hemispheric chemical dominance. Right hemispheric chemical dominance is a predisposing factor for Alzheimer's disease.

Topics: Aged; Albumins; alpha-Tocopherol; Alzheimer Disease; Ceruloplasmin; Digoxin; Dolichols; Dominance, Cerebral; Erythrocyte Membrane; Female; Free Radicals; Functional Laterality; Glycosaminoglycans; Humans; Hydroxymethylglutaryl CoA Reductases; Hypothalamus; Iron; Lysosomes; Magnesium; Male; Matched-Pair Analysis; Middle Aged; Phosphoprotein Phosphatases; Quinolinic Acid; Serotonin; Sodium-Potassium-Exchanging ATPase; Tryptophan

During aging the human brain shows a progressive increase in levels of dolichol, a reduction in levels of ubiquinone, but relatively unchanged concentrations of cholesterol and dolichyl phosphate. In a neurodegenerative disease, Alzheimer's disease, the situation is reversed with decreased levels of dolichol and increased levels of ubiquinone. The concentrations of dolichyl phosphate are also increased, while cholesterol remains unchanged. This study shows that the isoprenoid changes in Alzheimer's disease differ from those occurring during normal aging and that this disease cannot, therefore, be regarded as a result of premature aging. The increase in the sugar carrier dolichyl phosphate may reflect an increased rate of glycosylation in the diseased brain and the increase in the endogenous anti-oxidant ubiquinone an attempt to protect the brain from oxidative stress, for instance induced by lipid peroxidation.

Topics: Adult; Aged; Aged, 80 and over; Aging; Alzheimer Disease; Animals; Brain Chemistry; Cells, Cultured; Cholesterol; Dolichol Phosphates; Dolichols; Humans; Lipid Metabolism; Mevalonic Acid; Middle Aged; Nerve Degeneration; Polyisoprenyl Phosphates; Rats; Ubiquinone

Topics: Aging; Alzheimer Disease; Animals; Brain; Dolichols; Endopeptidases; Humans; Immunologic Techniques; Intermediate Filaments; Leucine; Leupeptins; Lipofuscin; Macaca fascicularis; Male; Protease Inhibitors; Rats; Rats, Inbred F344; Rats, Sprague-Dawley; Ubiquitins

The lipid compositions of 10 different brain regions from patients affected by Alzheimer's disease/senile dementia of Alzheimer's type were analyzed. The total phospholipid amount decreased somewhat in nucleus caudatus and in white matter. The cortical areas that are morphologically affected by Alzheimer's disease, i.e., frontal and temporal cortex and the hippocampus, showed elevated contents of lipid solvent-extractable phosphatidylinositol. Sphingomyelin content was decreased in regions rich in myelin. There was a 20-50% decrease in dolichol amount in all investigated parts of the brain, but no change was seen in the polyisoprenoid pattern. Levels of alpha-unsaturated polyprenes were decreased in Alzheimer brains. Dolichyl-phosphate content increased in most regions, up to 100%. In both control and Alzheimer tissue almost all of the dolichyl-phosphate was covalently bound, apparently through glycosylation. Cholesterol amounts were highly variable but mostly unchanged, whereas ubiquinone concentrations increased by 30-100% in most regions in brains affected by Alzheimer's disease. These results demonstrate that both phospholipids and neutral lipids are modified in brains affected by Alzheimer's disease/senile dementia of Alzheimer's type.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Brain Chemistry; Cholesterol; Dolichol Phosphates; Dolichols; Humans; Lipid Metabolism; Lipids; Nerve Tissue Proteins; Phospholipids; Ubiquinone

The lipid compositions of various regions of the human brain were investigated during aging and in Alzheimer's disease. The phospholipid amounts and compositions remained unchanged during aging. There were, however, considerable differences both in phospholipid composition and amount when the various regions were compared. The level of dolichol increased severalfold in all regions up to the age of 70, but there was no further elevation thereafter. The ubiquinone level decreased significantly in all parts of the brain upon aging. In Alzheimer's disease, the dolichol level was decreased in all regions, and particularly, in those affected by the disease. In contrast, the dolichyl-P concentration increased in those regions that exhibited morphological changes. There was no modification in cholesterol distribution, but a significant elevation in ubiquinone content was observed in most regions. The only phospholipid whose level was elevated was phosphatidylinositol, and only in those parts of the brain that were affected. The content of polyunsaturated fatty acids in phosphatidylethanolamine was greatly decreased in connection with the disease, with a parallel increase in the saturated portion. The results indicate that Alzheimer's disease results in specific and significant changes in the levels of lipid products of the mevalonate pathway in the brain.

Topics: Aged; Aging; Alzheimer Disease; Brain Chemistry; Cholesterol; Dolichol Phosphates; Dolichols; Fatty Acids; Humans; Membrane Lipids; Mevalonic Acid; Middle Aged; Phosphatidylinositols; Phospholipids; Ubiquinone

Quantitative analysis by HPTLC of the major lipid classes and dolichol, and of fatty acyl groups of separated phosphoglycerides by capillary GLC, has been carried out on the gray matter of frontal cerebral cortex of brains from six Down's syndrome (DS) and six Alzheimer's disease (AD) adults, and six each of two corresponding sets of age-matched controls; specimens of DS and control cerebellum and corpus callosum were also analyzed. In DS frontal cortex, but not in AD frontal cortex, compared to their respective controls there was a decrease in the fraction of phosphatidylethanolamine (PE) and an increase in the fractions of sphingomyelin (SPM) and phosphatidylserine (PS). Abnormalities were not found in the proportions of major lipid classes in DS cerebellum or corpus callosum. The concentration of dolichol was elevated for age in the frontal cortex of DS and of AD. In the phosphoglycerides of DS frontal cortex, the fatty acyl composition showed small, but statistically significant, differences from those of age-matched controls, and some slight abnormalities were also detected in DS corpus callosum. The alterations in DS frontal cortex included decreases in (n-6) and increases in (n-3) groups in choline and ethanolamine phosphoglycerides (CPG and EPG), as had previously been found in EPG and serine phosphoglyceride (SPG) of the DS fetal brain. In DS frontal cortex, the proportion of 22:4(n-6) groups was decreased in SPG, and in inositol phosphoglyceride (IPG) 18:1(n-9) was increased. There were also small but significant alterations in DS frontal cortex in the fractions of shorter chain groups in CPG. In marked contrast, most of the fatty acyl abnormalities seen in DS were absent in the AD frontal cortex. It is therefore suggested that some abnormalities in the composition of cerebral membranes present prenatally in DS may persist into adulthood, and are not directly related to AD-type pathology.

Topics: Acetals; Aged; Aged, 80 and over; Alzheimer Disease; Brain Chemistry; Cerebellum; Choline O-Acetyltransferase; Chromatography, Gas; Corpus Callosum; Dolichols; Down Syndrome; Esters; Fatty Acids; Frontal Lobe; Glycerophosphates; Humans; Lipids; Methanol; Middle Aged; Phospholipids

Although, compared to age-matched control samples, nonphosphorylated dolichols are significantly increased in the cerebral cortex of children with the late infantile and juvenile types of neuronal ceroid-lipofuscinosis (NCL), dolichyl phosphates are increased to a much greater extent in infantile, late infantile, and juvenile forms of this disease group. Dolichyl phosphates in the cerebral cortex, expressed as a percentage of the combined nonphosphorylated and phosphorylated compounds, ranged from 59 to 85 (mean 71) in NCL, whereas in the non-NCL disease group the range is 18-36 (mean 25). This marked proportional increase in dolichyl phosphates is not unique to NCL but is also found in the brain of GM1-gangliosidosis and Tay-Sachs disease patients. In the liver from NCL patients, dolichyl phosphates are not a major proportion of the total dolichol compounds (1-9%). However, in the kidney and heart, dolichyl phosphates are again markedly increased, and this is associated with large storage of ceroid. Although to a lesser extent than in NCL, dolichols and dolichyl phosphates are significantly increased over levels in age-matched control samples in the temporal cortex in Alzheimer disease. Our interpretation of these results is that storage in secondary in secondary lysosomes in NCL and the gangliosidoses leads to a decrease in the catabolism of dolichyl phosphate compounds in the Golgi saccules or primary lysosomes.

Topics: Alzheimer Disease; Brain Chemistry; Cerebral Cortex; Child, Preschool; Dolichol Phosphates; Dolichols; Humans; Infant; Kidney; Liver; Myocardium; Neuronal Ceroid-Lipofuscinoses; Polyisoprenyl Phosphates; Tay-Sachs Disease

Long-chain polyisoprenoid alcohols (dolichols) were measured in different brain regions dissected postmortem from 26 histopathologically confirmed cases of Alzheimer's disease and 24 age-matched nonAlzheimer control patients. They were significantly elevated in all parts of the cerebrum, but not in the cerebellum, of Alzheimer patients. The highest values were found in the temporal cortex and hippocampus. Out of the individual dolichol molecular species, the one with the most isoprene units (C105) was significantly increased in the temporal cortex, hippocampus, and basal forebrain of Alzheimer patients, compared with the controls. Dolichols were normal in the urinary sediment of 10 Alzheimer patients and nine patients with Down's syndrome, in comparison to age-matched controls for both groups. This is in contrast to neuronal ceroid-lipofuscinosis patients in whom dolichols are elevated in cerebral cortex, as well as in the cells of the urinary sediment, indicating generalized ceroid-lipofuscin storage.

Topics: Aged; Alzheimer Disease; Brain; Diterpenes; Dolichols; Down Syndrome; Humans; Middle Aged

Dolichols as unesterified alcohols were identified as significant components of lipid extracts from storage cytosomes isolated post-mortem from the brains of patients with the infantile, late infantile, and juvenile types of neuronal ceroid-lipofuscinosis (NCL). Very small amounts of dolichols were present in the corresponding subcellular fractions of non-NCL brains. The nuclear fraction from NCL cerebral cortex contained the highest dolichol content expressed per milligram protein or lipid, whereas the crude mitochondrial fraction was the richest in normal brain. Highly significant elevations of dolichol levels were found in human cerebral cortex of patients with NCL and Alzheimer's disease compared with age-matched controls, but the levels were normal in Pick's disease. In human non-NCL cerebral cortex, dolichols increased from 16 micrograms/g at age 5 to over 200 at age 81. Rat cerebral cortex showed a similar progressive increase in dolichol content with age. The high dolichol values in NCL, Alzheimer's disease, and senescence appears to be related to the increase of lipofuscin in brain. This is the first time a uniform biochemical abnormality has been found in all childhood forms of NCL, but the enzyme defect is still unidentified. It may lie on pathways where dolichols and retinyl compounds are recycled in Golgi membranes and derived organelles during the biosynthesis of glycoproteins.

Topics: Adolescent; Adult; Aged; Aging; Alzheimer Disease; Animals; Cerebral Cortex; Child; Child, Preschool; Cytoplasmic Granules; Dementia; Diterpenes; Dolichols; Humans; Microscopy, Electron; Middle Aged; Neuronal Ceroid-Lipofuscinoses; Rats; Reference Values; Subcellular Fractions

Topics: Aged; Aging; Alzheimer Disease; Cerebral Cortex; Chromatography, Liquid; Dementia; Diterpenes; Dolichols; Humans; Middle Aged