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Reference:
Science
The Mars Pathfinder issue
Dec 5, 1997, p. 1731
 

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Year 2001 update

Alzheimer's Amyloid b Protein and Lipid Metabolism

Essay for Pharmacia Biotech & Science Prize for Young Scientists

by Natalia V. Koudinova

27 June 1997

DEDICATION

To my father, Vladimir Yvanovich
( 16 June 1941 - 24 June 1997 )

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One of the major pathological markers of Alzheimer's disease (AD) and aged individuals is amyloid fibrils of brain senile plaques and cerebral blood vessels, composed primarily of an aggregated form of amyloid beta protein (Ab) [ 1 ]. Although there is a strong positive correlation between the number of amyloid plaques and the severity of memory loss, the precise effects of hydrophobic Ab in affected tissue are not known. Nevertheless, for a long time Ab was considered exclusively a pathological protein. But in 1992 it was identified as a soluble component (sAb) in culture media of different cell lines and in plasma and cerebrospinal fluid (CSF) obtained from normal and AD patients [ 2, 3, 4 ]. Moreover, the evolutionary conservation of Ab sequence among high eukaryotes [ 5 ] suggests its important physiological function(s). Since that time an understanding of normal molecular biology of Ab has been of highest priority in Alzheimer's research. 

The reported binding interaction of Ab with apolipoprotein (apo) E, apoJ, apoA-I and apoA-II [ 6, 7, 8, 9 ] allowed me to hypothesize that sAb in the circulation is complexed to lipoprotein particles (LP), of which these apolipoproteins are some of protein constituents. LP consists of a layer of phospholipids, unesterified cholesterol, and apolipoproteins surrounding a neutral lipid core of cholesterol esters and triglycerides [ 10 ]. Lipoproteins carry both substrates for the biochemical reactions of lipid metabolism (different lipids themselves) and the enzymes and their cofactors, necessary for these reactions. The latter is a function of different apolipoproteins which share unique structural properties. All apolipoproteins are amphipathic [ 11 ]. The amphipathicity explains an association of apolipoproteins' hydrophobic parts with lipids, in particular with nonpolar tails of phospholipids and nonesterified cholesterol. In these terms the reported evidence of amphipathicity of Ab molecule [ 12 ] provided a structural basis for the hypothesis of sAb association with lipoproteins. 

I tested this hypothesis in normal human CSF and showed that sA is associated with CSF high density lipoproteins (HDL) (Koudinov et al, 1996a, 1996b). These are the most dense human LP, enriched in apolipoprotein, phospholipid and unesterified cholesterol and lacking lipids of lipoprotein core [ 13 ]. 

SA association with HDL suggests a mechanism for maintaining peptide's solubility in biological fluids. It extends our current knowledge of sAb, specifying HDL as a structural component, where an interaction of Ab with other molecules take place. Of these molecules, apoE has been most attractive for scientists within the past few years. The reason is that apoE allele variant e4/e4 is a significant genetic risk factor for late-onset AD [ 14 ]. Proposed indirect mechanism of how inheritance of e4 might cause AD [ 15 ] suggests that apoE3, but not apoE4, can bind to tau protein, preventing it from abnormal phosphorylation. The latter process yields abnormally phosphorylated tau, the major component of intracellular neurofibrillary tangles, another important AD feature, which binds less well to the neuroskeleton microtubules, a process that could ultimately lead to the death of the neurons. Another explanation for the pathogenic role of apoE comes from in vitro studies, suggesting that apoE, particularly apoE4, promotes the fibrillogenesis of Ab [ 7, 8 ]. 

Nevertheless, the weak point of the described above mechanisms for the role of apoE in Alzheimer's disease is ignoring the major known function for apoE - its involvement in lipid, and in particular, cholesterol metabolism, changeswhich were suggested to be important in membrane destabilization as a mechanism for neurodegeneration in AD [ 16, 17 ]. Furthermore, it has been shown that there is a change in the function of a key enzyme of plasma cholesterol turnover, lecithin-cholesterol acyltransferase (LCAT) [ 18 ]. LCAT catalyzes an acyltransferase reaction which forms most of the cholesterol esters and is a key step in reverse cholesterol transport in humans. The enzyme circulates in blood in association with HDLs, which also carry sAb.  Moreover, sAb association with HDL suggests that peptide is involved in lipid metabolism, as are many other apolipoproteins [ 13 ]. 

Based on the described above observations I tested the effect of Ab on cholesterol esterification in normal human plasma, and showed that peptide possesses the inhibitory activity (Koudinov et al, 1996c). This observation led me to the issue of possible other function of Ab in lipid metabolism. The question addressed was "how are cellular effects of Ab in cell culture related to multiple lipid syntheses?" Treatment of HepG2 hepatoma cells with Ab decreased the syntheses of various radiolabeled lipid species from [14C]-acetate precursor (Koudinov et al, 1996d). The lipids whose synthesis was most decreased were cholesterol and phospholipids, the primary constituents of biological membranes affected in AD brain [ 19,20 ]. The inhibitory effect reached saturation at <10 to 100 ng of the peptide per 1 ml of media;  this may well reflect physiological modulation of lipid metabolism by Ab protein and represent one of the lipid related functions of sAb  as an apolipoprotein constituent of HDL [ 5 ]. On the other hand, the higher concentrations of  Ab (>100 ng/ml) are not likely to be reached under physiological condition, but may well represent local AD brain tissue environment. If the inhibitory effects of Ab, reported in the HepG2 cells, similarly take place in the brain tissue, it would suggest  an explanation of the reported changes in lipid composition in specific brain regions in AD [ 16, 17 ]. In addition, the differences in the effects of Ab on the metabolism of unesterified cholesterol (40% maximum inhibition) and phospholipid (25% inhibition) would clarify the cholesterol/ phospholipid mole ratio decrease in the AD brain versus age-matched controls, observed previously [ 20 ]. 

My data thus provide possible biochemical explanation for membrane destabilization secondary to a lipid compositional aberration as a mechanism for Ab-dependent neurodegeneration in AD. Still, the question of what is the primary event for this purported cascade remains obscure. Induction of Ab immunoreactivity in the brains of rabbits with enriched dietary cholesterol [ 21 ] suggests, assuming the concentration dependent inhibitory effect of Ab protein onto lipid biosynthesis, that an increase of Ab concentration within the affected
brain tissue might be secondary, and due to prior changes in lipid, particularly cholesterol, metabolism. Such induction of Ab deposition [ 21 ] may be the case in subjects, carrying the e4/e4 allele of apoE, shown to have elevated plasma cholesterol levels[ 22,23 ]. If this is true the therapeutical approach arraying the lipid metabolism correction in AD patients has to be of forthcoming priority.

References

1. Selkoe D. (1994). Alzheimer's disease: a central role for amyloid. J Neuropathol Exp Neurol 53: 438-447.

2. Shoji M, Golde T, Ghiso J, Cheung T, Estus S, Shaffer L, Cai X-D, McKay D, Tintner R, Frangione B, Younkin S. (1992). Production of the Alzheimer Amyloid b Protein by Normal Proteolytic Processing. Science 258: 126-129.

3. Haass C, Schlossmacher M, Hung A, Vigo-Pelfrey C, Mellon A, Ostaszewski B, Lieberburg I, Koo E, Schenk D, Teplow D, Selkoe D. (1992). Amyloid b-peptide is produced by cultured cells during normal metabolism. Nature (London) 359: 322-325.

4. Seubert  P, Vigo-Pelfrey C, Esch F, Lee M, Dovey H, Davis D, Sinha S, Schlossmacher M, Whaley J, Swindlehurst C, McCormack R, Wolfert R, Selkoe D, Lieberburg I, Schenk D. (1992). Isolation and quantification of soluble Alzheimer's b peptide from biological fluids. Nature (London) 359: 325-327.

5. Rosen D, Martin-Morris L, Luo L, White K. (1989). Drosophila gene encoding a protein resembling the human beta-amyloid precursor protein. Proc Nat Acad Sci 86: 2478-2482.

6. Wisniewski T, Frangione B. (1992). Apolipoprotein E: A pathological chaperone protein in patients with cerebral and systemic amyloid. Neurosci Lett 135: 235-238.

7. Strittmatter W, Saunders A, Schmechel D, Pericak-Vance M, Enghild J, Salvesen G, Roses A. (1993). Apolipoprotein E: High-avidity binding to b-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease. Proc Natl Acad Sci USA 90: 1977-1981.

8. Ma J, Yee A, Brewer H, Das S, Potter H. (1994).Amyloid associated proteins alpha 1 antichymotripsin and apolipoprotein E promote assembly of Alzheimer beta-protein into filaments. Nature 372: 92-94.

9. Matsubara E, Frangione B, Ghiso J. (1995). Characterization of Apolipoprotein J-Alzheimer's Ab Interaction. J Biol Chem 270: 7563-7567.

10. Davis R. (1991). Lipoprotein structure and secretion. In Biochemistry of Lipids, Lipoproteins and Membranes, D Vance and J Vance, eds. (Amsterdam: Elsevier Science Publishing Co.) pp. 403-426. 

11. Segrest J, Jackson R, Morrisett J, Gotto, A. (1974) A molecular theory of lipid-protein interaction in the plasma lipoproteins. FEBS lett 38: 247-253. 

12. Soreghan B, Kosmoski J, Glabe C. (1994). Surfactant properties of Alzheimer's Ab peptides and the mechanism of amyloid aggregation. J Biol Chem 269: 28551-28554.

13. Mahley R, Innerarity T, Rall S, Weisgraber K. (1984). Plasma lipoproteins: apolipoprotein structure and function. J Lipid Res 25: 1277-1294.

14. Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC, Small GW. (1993) Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late-onset families. Science 261: 921-23.

15. Strittmatter W, Weisgraber K, Goedert M, Saunders A, Huang D, Corder E, Dong L, Jakes R, Alberts M, Gilbert J, Han S-H, Hulette C, Einstein G, Schmechel D, Pericak-Vance M, Roses A. (1994). Hypothesis: Microtubule Instability and Paired Helical Filament Formation in the Alzheimer Disease Brain
Are Related to Apolipoprotein E Genotype. Exp Neurol 125: 163-171. 

16. Ginsberg L, Atack J, Rapoport S, Gershfeld N. (1993). Evidence for a Membrane Lipid Defect in Alzheimer Disease. Mol Chem Neuropathol 19: 37-46. 

17. Pettegrew J, Klunk W, McClure R, Panchalingam K, Strychor S. (1988). Phosphomonoesters, Phospholipids, and High-Energy Phosphates in Alzheimer's Disease: Alterations and Physiological Significance. In Alzheimer's Disease. New Treatment Strategies, Z Khachuturian and J Blass, eds. (Marcel Dekker, Inc.), pp. 200-205.

18. Knebl J, DeFazio P, Clearfield MB, Little L, McConathy WJ,  Pherson RMc, Lacko AG. (1994) Plasma lipids and cholesterol esterification in Alzheimer's disease.  Mech Aging Dev 73:  69-77. 

19.  Nitsch R, Blusztajn J, Pittas A, Slack B, Growdon J, and Wurtman R (1992). Evidence for a membrane defect in Alzheimer's disease brain. Proc Natl Acad Sci USA 89: 1671-1675.

20. Mason P, Shoemaker W, Shajenko L, Chambers T, and Herbette L. (1992). Evidence for Changes in the Alzheimer's Disease Brain Cortical Membrane Structure Mediated by  Cholesterol. Neurobiol of Aging 13: 413-419.

21. Sparks L, Scheff S, Hunsaker J, Liu H, Landers T, Gross D. (1994). Induction of Alzheimer-like b-Amyloid Immunoreactivity in the Brains of Rabbits with Dietary Cholesterol. Exp Neurol 126: 88-94. 

22. Czech, C.,  Forstl, H., Hentschel, F., Monning, U., Besthorn, C., Geiger-Kabisch, C.,  Sattel, H.,  Masters, C. and  Beyreuther, K. (1994). Apolipoprotein E-4 gene dose in clinically diagnosed Alzheimer's disease: prevalence, plasma cholesterol levels and cerebrovascular change.  Europ Arch Psych Clin Neurosci.  243: 291-292.

23. Jarvik, G., Wijsman, E., Kukull, W., Schellenberg, G., Yu, C. and Larson, E. (1995). Interactions of apolipoprotein E genotype, total cholesterol level, age, and sex in prediction of Alzheimer's disease: a case-control study. Neurology 45: 1092-1096.

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Koudinov, Alexei, R., Koudinova, Natalia, V., Kumar, Asok, Beavis, Ronald, and Ghiso, Jorge. (1996a). Biochemical characterization of Alzheimer's soluble amyloid beta protein in human cerebrospinal fluid: association with high density lipoproteins. Biochem Biophys Res Commun 223 (3), 592-597. 

Koudinova, Natalia, V., Koudinov, Alexei, R., Berezov, Temirbolat, T. (1996b). [Amyloid  b in plasma and cerebrospinal fluid is associated with high density lipoproteins]. [RUSSIAN]. Voprosy Meditsinskoi Khimii  42 (3), 253-262.

Koudinov, Alexei, R., Koudinova, Natalia, V., and Berezov, Temirbolat, T. (1996c). Alzheimer's peptides Ab1-40 and Ab1-28 inhibit the plasma cholesterol esterification rate. Biochem Mol Biol Internat. 38 (4), 747-752.

Koudinova, Natalia, V., Berezov, Temirbolat, T., and  Koudinov, Alexei, R. (1996d). Multiple inhibitory effects of Alzheimer's peptide Ab1-40 on lipid byosynthesis in HepG2 cells. FEBS Letters  395 (2-3), 204-206.

Text copyright © 1997-2001 by Natalia Koudinova


2001 update
 

Additional credit:
The above essay is the basis of the FASEB Journal (1998) commentary

This essay or any it part may be reproduced without Natalia Koudinova permission in case your report includes citation of the article source, Natalia Koudinova name and you let us know where your report will appear or has appeared.

To cite this article use:
N.V. Koudinova. (1997) Alzheimer's Amyloid b protein and Lipid Metabolism. Essay for the Science Magazine and Pharmacia Biotech Prize for Young Scientists 1997.

Epilogue:

Four years and four months later the subject of "Cholesterol, amyloid b and Alzheimer's disease" was officially approved as new science focus (see Science  magazine October 19, 2001  issue)
[ PubMed ] [ Full text ]


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