Alzheimers amyloid beta and lipid metabolism a missing link

COMMENTARY Alzheimer’s amyloid beta and lipid metabolism: a missing link? ALEXEI R. KOUDINOV,*,1 TEMIRBOLAT T. BEREZOV, AND NATALIA V. KOUDINOVA* Weizmann Institute, Department of Neurobiology, Rehovot, 76100 Israel* and Russian Academy of Medical Sciences, Institute of Biomedical Chemistry and Russian Peoples’ Friendship University School of Medicine, Department of Biochemistry, Miklucho-Maklay St., 8, Moscow, 117198 Russia THE EXCELLENT ARTICLE by Baggio et al. was of particular interest to us because it addressed an important issue pertaining to our special subject of Alzheimer’s research: the ‘‘hypothesis that a continuous reshaping in lipid physiology occurs with age and is a critical factor for survival and successful aging.’’ (1) The authors are correct that ‘‘changes in the serum level of protein, lipids, and lipoproteins that are considered risk factors for atherosclerotic vascular diseases in young people may lose their biological significance and assume a different, unknown role with advanced age.’’ But we are beginning to learn that blood lipids are indeed associated with Alzheimer’s disease (AD)2 and our group and others are discovering that Alzheimer’s may be very closely linked to human lipid metabolism change. First, it has been shown (2) that the lecithin cholesterol acyl transferase (LCAT) activity is significantly decreased in Alzheimer’s patients. LCAT catalyzes an acyltransferase reaction that forms most of the cholesterol esters and is a key step in reverse cholesterol transport in humans. This makes the enzyme of obvious significance in the development of atherosclerosis and heart disease. Moreover, as was demonstrated a decade ago (3), this is also the case with Down’s syndrome (DS), where there are the same blood changes in LCAT activity. This indicates that changes in this enzyme are related to the etiologies of both AD and DS on the one hand and vascular pathology on the other. In addition, there is a remarkable resistance to systemic atherosclerosis in DS (4), which is not yet shown in AD. Second, it has been proposed (5) that membrane destabilization in Alzheimer’s disease as a natural consequence of primary defective lipid composition (5) is important in the membrane damage that leads to brain cell death. The membrane destabilization was found to occur selectively at the areas of neurodegeneration in AD brain, thus potentially accounting for the localized lipid pathology. Our own research activities are focused on understanding in more detail the normal biology of Al0892-6638/98/0012-1097/$02.25 FASEB zheimer’s amyloid beta protein (Ab). This small protein has a high tendency to form insoluble amyloid aggregates. Amyloid deposition of cerebrovascular amyloid and senile plaques is a characteristic feature of the Alzheimer’s brain and the latter was reported to occur in the brain of heart disease patients (6, 7). Nevertheless, in 1992 it became clear that Ab is not just a pathological protein. At that time several research groups (8–10) detected it in a ‘normal’, soluble (sAb), nonaggregated state in blood and cerebrospinal fluid (CSF) of both normal people and patients with AD. The question why this protein does not aggregate normally became of special interest to many Alzheimer’s research teams. Published data regarding Ab binding to a number of proteins, and in particular to apolipoproteins in a test tube (11, 12), led us to a hypothesis that these interactions reflect an sAb association with lipoproteins, of which apolipoproteins are protein constituents. Evidence described in our recently published papers (13–15) indicates an association of sAb with special class of normal blood and CSF lipoproteins, high density lipoproteins (HDL), believed to be a protective factor in atherosclerotic vascular disease. Furthermore, sAb is secreted by hepatic cells as a part of lipoprotein complex (16). Association of Alzheimer’s amyloid beta with HDL suggests a mechanism for maintaining it in normal soluble, not aggregated state in blood and body fluids of normal individuals (13–15). Moreover, HDL carry LCAT, the key enzyme of cholesterol removal from the body, activity that in the disease is changed (see above). On the basis of the observations described above, we tested the effect of Ab on cholesterol esterification Correspondence: Weizmann Institute of Science, Department of Neurobiology/Jaglom, Rehovot 76100, Israel. E-mail: koudin@imb.imb.ac.ru 2 Abbreviations: LCAT, lecithin cholesterol acyl transferase; AD, Alzheimer’s disease; DS, Down’s syndrome; CSF, cerebrospinal fluid; HDL, high density lipoproteins; Ab, amyloid beta protein; sAb, soluble amyloid beta protein. 1097 1 / 382f 0008 Mp 1097 Friday Jul 31 03:33 PM LP–FASEB 0008 in normal human plasma and showed that peptide possesses the inhibitory activity (17). This observation led us to the issue of possible other function of Ab in lipid metabolism. 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 (18). 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 õ10 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. On the other hand, the higher concentrations of Ab (ú100 ng/ml) used in the study 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 might explain the reported changes in lipid composition in specific brain regions in AD (5). 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 (21). The experimental evidence described above suggests that continuous reshaping in lipid physiology occurring with age is closely linked to AD, and that this linkage is part of Alzheimer’s pathophysiology rather than a consequence. Notable, lipid and Ab metabolism change may explain some important disease features, like apoE allele variant e4/e4 significance as a genetic risk factor for late-onset AD (22). Thus, induction of Ab immunoreactivity in the brains of rabbits with enriched dietary cholesterol (23) suggests, assuming the concentration dependent inhibitory effect of Ab protein onto lipid biosynthesis (18), that an increase of Ab concentration within the affected brain tissue might be secondary, and due to previous changes in lipid, particularly cholesterol, metabolism. Such induction of Ab deposition (23) may be also the case in subjects, carrying the e4/e4 allele of apoE, shown to have elevated plasma cholesterol levels (24, 25). Still, the question of what is the primary event for this purported cascade remains obscure and many other questions remain, which is why we are working hard to bring us closer to solving this part of lipid gerontology and the Alzheimer’s mystery in order to alleviate human suffering. This research was supported by National Institutes of Health grants AG10953 and AG08051, Senetek PLC., Russian Acad1098 Vol. 12 September 1998 emy of Medical Sciences, Israeli Science Foundation, and Feinberg Fellowship. Part of this research was presented as an essay for the Pharmacia and Science Prize for Young Scientists by Natalia Koudinova, named a finalist in the 1997 competition (26). We thank Drs. H. Kayden, B. Frangione, J. Ghiso, G. Gallo, A. Kumar, B. Raaka, H. Samuels, V. Nussenzweig, M. Segal, E. Yavin, and F. Hitchcock and E. Curley for encouragement and continuous support. REFERENCES 1. Baggio, G., Donazzan, S., Monti, D., Mari, D., Martini, S. Gabelli, C., Dalla Vestra, M., Previato, L., Guido, M., Pigozzo, S., Cortella, I., Crepaldi, G., and Franceschi, C. (1998) Lipoprotein(a) and lipoprotein profile in healthy centenarians: a reappraisal of vascular risk factor. 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