BRAIN CHOLESTEROL PATHOLOGY IS THE CAUSE OF …

To read web enhanced article and provide comments, go to: http://clinmed.netprints.org/cgi/content/full/2001100005v1 To cite this article, use: Clin Med Health Res (2001) clinmed/2001100005

Reprint value 100 $ Copyright © 2001 by Alexei Koudinov and Natalia Koudinova. Published online with the assistance of BMJ

http://clinmed.netprints.org

BRAIN CHOLESTEROL PATHOLOGY IS THE CAUSE OF ALZHEIMER’S DISEASE Alexei R. Koudinov1CA & Natalia V. Koudinova1,2

1 Berezov Academic Laboratory, Russian Academy of Medical Sciences, Timoshenko St., 38-27, Moscow, ..121359 Russia; 2 Weizmann Institute of Science, Department of Biological Regulation, Rehovot, 76100 Israel

First submitted: January 5, 2001, Published online: November, 2001

CACorresponding author: Alexei R. Koudinov, P.O.Box 1665, Rehovot 76100 Israel Tel: (972 8) 947-1803; Fax: (972 8) 934-4116; Internet: [email protected]; http://anzwers.org/free/neurology/ Keywords: amyloid beta protein precursor, Down syndrome etiology, learning and synaptic plasticity, lipoprotein LDL LRP receptor, neurodegeneration marker, oxidative stress, PHF tau phosphorylation

Several recent reports provided important knowledge on how “inhibiting cholesterol production in the brain might inhibit amyloid β (Aβ) production, and reduce the accumulation of Aβ that causes Alzheimers disease (AD)”.1WEB+,2 As we show and discuss here cholesterol homeostasis biological misregulation itself has a key role for synaptic plasticity impairment, neuronal degeneration and is the primary cause for several AD hallmarks not limited to brain amyloid. Moreover, Alzheimer's changes in neurochemistry of Aβ, tau, neuronal cytoskeleton, and oxidative stress reactions likely represent physiological transitory mechanisms aiming to compensate impaired brain cholesterol dynamics and/or associated neurotransmission and synaptic plasticity failure.

CLINICAL AND EXPERIMENTAL STATE OF THE ART: CHOLESTEROL AND ALZHEIMER’S

HALLMARKS

Todate, many reports implicate cholesterol in AD. Thus, two turn-of-the-century reports showed that statins (an inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, cata-

lyzing the early rate-limiting reaction in cholesterol biosynthesis) protect against dementia3 and AD4 prevalence. An accompa-nying commentary5 of the latter paper drew a possible scenario “whereby increased plasma cholesterol concentration through the increased net sterol turnover to the brain enhances the production of Aβ protein and neuritic plaques, the key histochemical feature of the disease”. This possibility seems strengthened by acceleration of brain amyloid pathology in mutant human amyloid precursor protein transgenic mice6 and rabbits7 with dietary hypercholesterolemia and by learning impairment in rats with manganese-induced hypercholesterolemia.8 However, several studies failed to show a difference in risk of dementia or AD based on serum cholesterol concentrations3 and statins were experimentally shown to specifically correct brain cholesterol levels in rodents.8,9 Moreover, a number of reports demonstrated no role for plasma cholesterol in the brain cholesterol turnover.10,11 Furthermore, rats (lab animals most resistant to dietary hypercholesterolemia12) under the condition of cholesterol feeding have all brain cholesterol newly synthesized10,13 while cholesterol bio-synthesis in the liver is suppressed.14

In accord with the above papers6,7,15 and despite of tolerating hypercholesterolemia12 albino wistar rats fed a cholesterol diet demonstrate increased cholesterol and phospholipid synthesis in the hippocampus

Koudinov and Koudinova: Brain Cholesterol Pathology is the Cause of Alzheimer’s Disease

Clinical Medicine and Health Research, November, 2001, clinmed/2001100005v1

2

(Fig.1, Table) and are characterized by Alzheimer’s-like amyloid (Figs. 1B,C,E; thus being a phenomenon secondary to brain cholesterol abnormality and possible aiming to modulate impaired neural cholesterol dynamics11,15, see below) and impaired long-term potentiation (LTP, Fig. 1F), a long-lasting plastic changes of synapses that underlie learning and memory.8,11 Moreover, impaired synaptic plasticity in rat ex-vivo hippocampal slices is caused by experimentally inhibited cholesterol synthesis17 or increased cholesterol efflux.11 The later condition in vivo may well be due to functionally, abnormally or experimentally increased rate of brain cholesterol synthesis (Fig.1) and associated turnover upregulation.18

The experimental condition of increased cholesterol efflux is also characterized by paired helical filaments (PHF)-tau hyperphospho-rylation in neurofibrillary tangles (NFT) and neurite degeneration,11 another key histo-chemical feature of AD. The observation of cholesterol-dependent tau phosphorylation in ex-vivo hippocampal slices11 and in cultured neurons,19WEB+ as well as higher values of intracellular cholesterol in NFT-bearing neurons of AD cortex,20 the Alz-50 (an antibody that recognizes tau in NFTs) immunoreactivity in the brain of cholesterol-fed rabbits7 suggest that NFT formation is a secondary phenomenon of abnormal neuronal cholesterol homeostasis.

CHOLESTEROL, SYNAPTIC FUNCTION AND ALZHEIMER’S

DISEASE

While no transport of cholesterol to the brain from the circulation is described, neural cells replenish their cholesterol by intracellular cholesterol synthesis, the release from the ester storage pool, and intrabrain extracellular lipoprotein-mediated cholesterol transport.21-23 Comparing with the rest of the body, the brain (having about a quarter of an individual whole body cholesterol while comprising just two percent of the body mass5,21WEB+) must maintain an exceptional efficiency of neural cholesterol homeostasis, dictated by dynamic plastic structural changes of neurons and their synapses, accompanying neurotransmission, synaptic plasticity and memory formation.11,22 The complex processes that neural cells must coordinate include lipoprotein receptor-mediated cholesterol influx; intracellular transport, compartmentation, and metabolism; efflux to a suitable acceptor; extracellular redistribution; and reverse cholesterol transport,11,21-23 a cholesterol export out of the brain and CSF to

plasma and liver for its disposal into bile. These processes are regulated by a number of proteins, including lipoprotein receptors; enzymes involved in cholesterol biosynthesis, degradation and esterification; transcriptional regulatory proteins; and apolipoproteins implicated in lipo-protein-mediated cholesterol transport.2,11,21,23,24 ccccConceivable, the break in any element of this harmonized system (caused by genetic defects of one of the associated proteins or by non-genetic [environmental, for example] factors) may result in abnormal homeostasis of cholesterol in the brain, impair fine tuning of neuronal function, and cause Alzheimer’s-like neurodegeneration features (Fig.1).6,8,11,15,17,25-27WEB+ Importantly, crosstalk of hepatic and neuronal chole-sterol10,12-14 (see previously) makes systemic cholesterol imperfection an important factor in developing brain cholesterol homeostasis failure. Several clinical and experimental reports favor relevance of the drawn possibility to the disease. Thus, first, AD is characterized by reduced cholesterol esterification,28-30 implying an abnormal CSF high density lipoprotein inter-conversion, critical for extracellular cholesterol trafficking and reverse cholesterol transport.23 Second, AD is characterized by activation of the pathway for cholesterol removal out of the brain based on its’ oxidative conversion into 24S-hydroxycholesterol,18 indicating insufficiency and/or saturation of lipoprotein-mediated cholesterol disposal.23 Third, cholesterol accumulates in senile plaques of AD patients and in plaque-like amyloid of aged mutated amyloid precursor protein transgenic mice,31 suggesting the interrelation of the repartitioning of cholesterol in the brain and amyloid deposition. Forth, human ApoE ε4/ε4 knock-in mice have markedly altered systemic and brain cholesterol metabolism,32 offering cholesterol trafficking attenuation as an explanation for the increased AD risk in ApoE ε4/ε4 subjects. Fifth, recent observation documented significant elevation of the LDL receptor related protein levels in AD frontal cortex33 opening the possibility of upregulation or insufficiency of lipoprotein-receptor-mediated neuronal cholesterol redistribution in the disease.11,18,23 Finally, related to AD Down syndrome (DS), a trisomy 21, is copying Alzheimer’s cholesterol esterification abnormality.34 DS is also characterized by a specific pathway of the liver sterol regulatory element binding protein (SREBP) activation with sterol-independent maturation of SREBP-1, and by high circulating and tissue cholesterol levels in the fetuses,35 implying importance of developmental fetal cholesterol pathology for earlier (compared to AD) genesis of Alzheimer’s features in trisomy 21 subjects.



3

Figure 1. Brain cholesterol homeostasis biological misregulation causes synaptic plasticity failure and Alzheimer’s-like amyloid pathology: an experimental evidence. Up to the present there were no understanding of the role of cholesterol in the etiology of Alzheimer’s disease (AD) and in the disease causation relation. By feeding albino wistar rat a cholesterol diet we generated an animal model, characterized by upregulated brain cholesterol and phospholipid synthesis, plaque and vascular amyloid, and reversible synaptic plasticity failure. Two-month old male albino Wistar rats (200-250 g, raised in a local breeding colony of the Weizmann Institute of Science, Rehovot, Israel, managed by Harlan Laboratories, Israel) were kept at the departmental animal facility in an environment of low background noise, constant temperature (230C) and alternating lighting (lights on 7am–7pm). Control and experimental rats (n=8 animals in two experimental sets) were fed normal diet and identical diet supplemented with 2 % cholesterol (Sigma), respectively, for 4-6 months prior to the experiments reported below. Consistent with previous data10,12-14 by chronic modification of adult albino Wistar rat cholesterol status with a cholesterol diet we generated an animal model, characterized by significantly increased hippocampal synthesis of cholesterol and phospholipids, two major lipid components of the membranes of any living cell and of neurons, where nervous system activity is generated and propagated. We investigated cholesterol and different phospholipids syntheses in ex-vivo hippocampal slices of cholesterol-fed and control rats by incorporation of [14C]-acetate precursor into the newly synthesized lipid species, followed by lipid extraction, lipid separation by TLC, and radioactivity counting. This experimental protocol was previously employed and adapted for the ex-vivo brain slices.11 In all cases the data were presented as lipid-incorporated radioactivity, mean±SEM (n=6). As illustrated in the Table, cholesterol diet significantly upregulated hippocampal and cortical (not shown) cholesterol (chl) and all tested phospholipid syntheses (Mann-Whitney test, P<0.05, one tailed), indicating that dietary cholesterol causes brain cholesterol turnover upregulation in cholesterol-fed rats.10,12-14 PC, PE, PI and PS designate phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol and phosphatidylserine, respectively. The following immunohistochemical analysis and electrophysiological experiments were performed as we detailed previously.11,16 Panels A-E show extracellular immunohistochemical staining of Aβ with 4G8 (1:1000) monoclonal antibody11 (anti-rodent/humanAβ17-24) in brain sections of cholesterol fed rats (B, C, E). Alzheimer's-like plaque amyloid (B, C) and vascular Aβ deposition (E) are illustrated in the hippocampus (E) and cortex (B, C). Panels A and D represent control rat cortical and hippocampal fields, respectively. Bar, 50 µM for panels A-C; and 30 µM for panels D, E. Panel F demonstrates impairment of tetanus induced long term potentiation (LTP) in CA1 of ex-vivohippocampal slices in cholesterol-fed rats (squares, n=8 slices) versus control animals (circles, n=12). LTP, a characteristic of synaptic plasticity,11,16 was expressed as a normalized field excitatory postsynaptic potential (fEPSP) slope change versus time. Arrow indicates the time of tetanic stimuli train. Note that reversal of cholesterol diet to control diet for 5 weeks caused significant (P<0.05, one tailed) reversal of LTP impairment (triangles, n=5). Presented data thus provide experimenal evidence that hippocampal cholesterol dynamics dysfunction causes Alzheimer’s major functional phenomenon of synaptic plasticity impairment and major pathological hallmark of amyloid deposition. Impairment of neurotransmission and synaptic plasticity in acute model of brain cholesterol pathology11 (that lacks Aβ deposition) indicates that cholesterol (and not Aβ) misregulation is a primary cause of synaptic dysfunction. Moreover, as lipid metabolism functional player, Aβ likely modulates its biology in presented here chronic model of cholesterol-fed rat in order to recover impaired brain cholesterol homeostasis (see below).



4

Scheme 1. Schematic representation of the sounded here cascade of the common sporadic forms of Alzheimer’s disease (AD). Brain/neuronal cholesterol homeostasis misregulation causes the key AD feature of learning and memory failure as a result of the impairment of neuronal function, neurotransmission and synaptic plasticity through the mechanisms precise molecular nature which remains to be identified.8,11,17,27WEB+ Cholesterol-mediated change in neurochemistry of amyloid beta, 6,7,36,FIG.1 tau phosphorylation,11,19,48WEB+ neuronal cytoskeleton rearrangements11,19WEB+ and the modulation of physiological equilibrium of oxidative stress reactions15 could provide physiological transitory mechanisms aiming to compensate impaired brain cholesterol dynamics andneurotransmission and synaptic plasticity (see text and Ref. 11 for additional discussion of the above statement). The break in neural cholesterol homeostasis may require very long (i.e. chronic) onset time frame due to the physiologically slow turnover of the central nervous system (CNS) cholesterol. Such condition may be genetically set (right top) and be assisted environmentally by the long term dietary habits. While during the past 30 years the concept of healthy food has become synonymous with avoiding dietary cholesterol,49 the question of how this avoidance and its compensation affects brain cholesterol chemistry, learning and memory remained non-addressed for many years. Several basic reports, however, documented that brain cholesterol is a delicate substance very sensitive to many influences, ranging from lipid preparation diets and chemical delivery systems for drugs and food additives (cyclodextrins, for example11) to learning process itself.50WEB+ It is thus possible that antifat lifestyle “soft science” doctrine49 contributed to the increase in dementia and AD prevalence in industrialised countries51 during 1970s and 1980s.52WEB+ The indicated physiological compensatory changes may slowly invert when neuronal cholesterol dynamics is recovering slow to the initial physiological level. Such reversibility was proved experimentally36,50,53,FIG.1 and certified by nature as an important mechanism of the CNS plasticity, as exampled by high expression of PHF-phosphorylated tau during an ontogenic period of cholesterol-demanding intense neuritic outgrowth.48WEB+ General compensatory nature of Aβ and tau neurochemistry modulation was proposed previously54 and is illustrated by its change observed under related to cholesterol (but different from AD) cardiovascular and Niemann-Pick type C pathologies, as well as in normal cases and during aging.11,41,55WEB+ When neuronal cholesterol dynamics is not recovering compensatory mechanisms fail yielding (yet possible reversible48WEB+,53) the development of conventional AD hallmarks (right). These hallmarks, however, are not causative for the sporadic AD, and thus unlikely represent the proper target for the efficient AD therapy,54 as supported by the cognitive decline and dementia in AD patients without detectable lesions.56

Of these disease markers demonized amyloid beta pathology is the key enemy for the amyloid cascade hypothesis. As recently confirmed, plaque amyloid itself impairs (dotted arrows) synaptic plasticity and learning,57,58 neural networks,59 protein phosphorylation and oxidative stress status.60 Plaque amyloid therefore may have separate pathogenetic significance for the rare genetic familial forms of AD, caused by the mutations in amyloid precursor protein and presenilins genes. Similarly, oxidative stress independently disrupts synaptic plasticity61,62 and thus may have separate pathogenic value for the Down syndrome (characterized by upregulation of the reactions of oxidative stress due to the possible overexpression of the enzyme Cu/Zn-superoxide dismutase (SOD1), a chromosome 21 gene product) and for the pre-plaque stages of AD.63 The hallmarks trigger third order events of microglia activation, astrocytosis, cytokine/acute-phase protein release and cell death (not shown). This may convert physiological compensation into the pathological final and lock the cascade and the disease irreversibility.

Three reasons to read web enhanced vesrion of this article online

Å To turn this article into your desktop reference center by

instant access to abstracts and full text of 71 citations, 13

WEB+ and 11 supplementary web-only references, and 8

eLetters to editor.

Ç To participate in free

unlimited online discussion of this article and the subject of

cholesterol, neuronal function, synaptic plasticity,

amyloid beta, tau, Alzheimer’s disease and

other related topics at the exclusive ClinMed web site.

É To learn what is the New Millennium biomedical

science publishing and how you can prepare, submit and

have your next original research article published at

ClinMed NetPrintsTM



5

CHOLESTEROL AND AMYLOID BETA PROTEIN

Todate, the role of cholesterol in AD is mainly discussed in the context of the reduction of amyloid burden by lowering chole-sterol.1WEB+,2,5,6,36 This viewpoint is based on more then dozen reports implicating cholesterol in amyloid precursor protein processing and Aβ generation in cell cultures and in laboratory animals (for these supplementary web-only references see web enhanced article version). Two recent articles2,41 further showed that cellular generation of Aβ is modulated by cholesterol compartmentation and intracellular cholesteryl-ester levels. The biochemical relation of cholesterol and Aβ, however, is bidirectional, and the modulation of neuronal cholesterol dynamics by Aβ likely has important functional consequences. Particularly, Aβ modulates neuronal cholesterol esterification,37,38 influx,11,39 and efflux,23,40 and thus possibly regulates neural cholesterol intracellular compartmentation and extracellular trafficking.21WEB+,23,40,41 Aβ also modulates neuronal physical property of membrane fluidity42,43 suggested to be important for cholesterol-dependent cell receptor machinery impairment (discussed in Ref. 11). Additionally, Aβ increases lipid synthesis (specifically that of cholesterol and phospholipids) in PC12 and rat primary neuronal cell cultures, fetal brain, and in ex vivo hippocampal slices,11,44,45 in contrast to the peptide inhibitory (and cholesterol lowering46) effect, observed in human hepatic HepG2 and in HEK293 cells, in fetal rat liver and in neuronal tissue under the condition of potassium-evoked depolarization and under oxidative stress.30,44-46

The latter results highlight the importance of developmental, tissue and neuronal functional specificity of Aβ-cholesterol biochemical relation, which may vary in different brain regions and be of special importance in determining Alzheimer's specific areas of neurodegeneration.30,44-46 These data also suggest that Aβ may serve a molecular messanger function and manage the crosstalk of hepatic, systemic and brain cholesterol, and thus maintain the tissue-specific coordinate regulation of cholesterol biosynthesis.10,12-14 Taken together, the above functional consideration and recent data on the importance of cholesterol compartmentation for Aβ generation2,41 indicate feedback functional relation between cholesterol and Aβ homeostasis, additionally supported by a dependency of amyloid precursor protein

processing and Aβ production on the site 2 processing of SREBP47 (the major regulatory protein in cholesterol metabolism21WEB+,24,35) and associated inability of cells to upregulate the expression of several enzymes and proteins involved in cholesterol synthesis and turnover.47

CONCLUSION

We believe that the fundamental pathophysiological event in most common sporadic forms of AD is

accurate brain cholesterol homeostasis failure

(See Scheme 1)

It is advocated by the fact that neuronal cholesterol pathology is a sufficient event to cause major Alzheimer’s features of excessive tau phosphorylation,7,11,19WEB+,20 amyloid forma-tion,2,6,7,41,FIG.1 neurite degeneration,11,19,55WEB+ neuronal cell death,64 cholinergic dysfun-ction,25,26 oxidative stress15 and synaptic11,17,65,27WEB+ (also see previously) and behavioral8,66,67 impairment. Yet further studies are needed to better understand normal and pathologic functional biochemistry of brain cholesterol68,69 in order to strengthen such Alzheimer’s causation relation or to disprove it. If proved, an intelligent neuronal cholesterol perfection may become pathologically grounded therapeutic approach aiming the disease cause. Recent clinical data,3,4 experimental cholesterol correction-dependent reversal of neural amyloid density1WEB+,2,36,53 and synaptic (Fig. 1) and behavioral8 dysfunction reserve a hope and alarm on the need of concentrating efforts on cholesterol front of Alzheimer’s battle in addition (or contrast?) to yet failed to bring AD cure 15-years-long amyloid odyssey.

ACKNOWLEDGMENT

For support and funding itemization see Ref. 11. Earlier version of this article was prepared during December 2000 as invited hypothesis manuscript for The Lancet. This article was also submitted as viewpoint to Trends in Neurosciences, Proceedings of the National Academy of Sciences USA, Neuron, New England Journal of Medicine, Nature Cell Biology and Nature Review Neurosciences. Lately, based on one reviewer comment, the manuscript was



6

rejected from Archives of Neurology where it was submitted by invitation. We appreciate British Medical Journal editorial staff for the idea to publish this article in Clin Med Health Res. This research was reported at the 30th and 31st Annual Meetings of the Society for Neuroscience (Nov. 5, 2000, New Orleans, LA, and Nov. 11-15, 2001, San Diego, CA, respectively) as scientific70 and teaching71 posters and press book lay language summaries. Our research is dedicated to our parents.

REFERENCES

1. Marx J. Alzheimer's disease: bad for the heart, bad for the mind? Science. 294, 508-509 (2001).

2. Puglielli L, Konopka G, Pack-Chung E, et al. Acyl-coenzyme A: cholesterol acyltransferase modulates the generation of the amyloid beta-peptide. Nat. Cell. Biol. 10, 905-912 (2001).

3. Jick H, Zornberg GL, Jick SS, Seshadri S, Drachman, D.A. Statins and the risk of dementia. Lancet. 356, 1627-1631 (2000).

4. Wolozin B, Kellman W, Ruosseau P, Celesia GG, Siegel G. Decreased prevalence of Alzheimer disease associated with 3-hydroxy-3-methyl-glutaryl coenzyme A reductase inhibitors. Arch Neurol. 57, 1439-1443 (2000).

5. Haley RW, Dietschy JM. Is there a connection between the concentration of cholesterol circulating in plasma and the rate of neuritic plaque formation in Alzheimer disease? Arch Neurol. 57, 1410-1412 (2000).

6. Refolo LM, Pappolla MA, Malester B, et al. Hypercholesterolemia accelerates the Alzheimer’s amyloid pathology in a transgenic mouse model. Neurobiol Dis. 7, 321-331 (2000).

7. Sparks DL. Induction of Alzheimer-like beta-amyloid immunoreactivity in the brains of rabbits with dietary cholesterol. Exp Neurol. 126, 88-94 (1994).

8. Senturk UK, Oner G. The effect of manganese-induced hypercholesterolemia on learning in rats. Biol Trace Elem Res. 51, 249-257 (1996).

9. Eckert GP, Kirsch C, Muller WE. Differential effects of lovastatin treatment on brain cholesterol levels in normal and ApoE-deficient mice. Neuroreport. 12, 883-887 (2001).

10. Edmond J, Korsak RA, Morrow JW, Torokboth G, Catlin DH. Dietary-cholesterol and the origin of cholesterol in the brain of developing rats. J Nutrition. 121, 1323-1330 (1991).

11. Koudinov AR, Koudinova NV. Essential role for cholesterol in synaptic plasticity and neuronal degeneration. FASEB J. 15, 1858-1860 (2001), originally published online June 27, 2001, 10.1096/fj.00-0815fje

Cited above companion article is a prologue for this report. It discusses the role for cholesterol, Aβ

and tau in synaptic function and plasticity

12. Roach PD, Balasubramaniam S, Hirata F, et al. The low-density lipoprotein receptor and cholesterol synthesis are affected differently by dietary cholesterol in the rat. Biochim Biohys Acta. 1170, 165-172 (1993).

13. Morell P, Jurevics H. Origin of cholesterol in myelin. Neurochem Res. 21, 463-470 (1996).

14. Spady DK, Cuthbert JA. Regulation of hepatic sterol metabolism in the rat. Parallel regulation of activity and mRNA for 7 alpha-hydroxylase but not 3-hydroxy-3-methylglutaryl-coenzyme A reductase or low density lipoprotein receptor. J Biol Chem. 267, 5584-5591 (1992).

15. Sparks DL. Increased cholesterol in AD and cCAD cortex, and increased cholesterol content and free radical enzyme activity in rabbit brain due to dietary cholesterol. J Neuropath Exp Neurol. 55, 51 (1996).

16. Friedman LK, Koudinov AR. Unilateral GluR2 (B) Hippocampal Knockdown: A Novel Partial Seizure Model in Young Rat. J Neurosci. 19, 9412-9425 (1999).

17. Matthies H, Schulz S, Hollt V, Krug M. Inhibition by compactin demonstrates a requirement of isoprenoid metabolism for long-term potentiation in rat hippocampal slices. Neurosci. 79, 341-346 (1997).

18. Papassotiropoulos A, Lutjohann D, Bagli M, et al. Plasma 24S-hydroxycholesterol: a peripheral indicator of neuronal degeneration and potential state marker for Alzheimer’s disease. Neuroreport. 11, 1959-1962 (2000).

19. Fan QW, Yu W, Senda T, Yanagisawa K, Michikawa M. Cholesterol-dependent modula-tion of tau phosphorylation in cultured neurons. J Neurochem. 76, 391-400 (2001).

20. Distl R, Meske V, Ohm TG. Tangle-bearing neurons contain more free cholesterol than adjacent tangle-free neurons. Acta Neuropathol (Berl). 101, 547-554 (2001).

21. Fielding CJ, Fielding P. Intracellular cholesterol transport. J Lipid Res. 38, 1503-1521 (1997).

22. Poirier J, Baccichet A, Dea D, Gauthier S. Cholesterol synthesis and lipoprotein reuptake during synaptic remodelling in hippocampus in adult rats. Neurosci. 55, 81-90 (1993).

23. Koudinov AR, Berezov TT, Koudinova NV. The levels of soluble amyloid beta in different HDL subfractions distinguish Alzheimer's and normal aging CSF: implication for brain cholesterol pathology? Neurosci Lett. 314, 115-118 (2001).

The above article discusses how an impairment of extracellular lipoprotein-mediated trafficking of

brain cholesterol may be linked to synaptic function, neural apolipoproteins and AD

24. Brown MS, Goldstein JL. The SREBP pathway:

regulation of cholesterol metabolism by proteolysis of a membrane-bound transcription factor. Cell. 89, 331-340 (1997).

25. Crews FT, Camacho A, Philips MI. Cholinergic stimulation of hippocampal pyramidal cells is inhibited by increasing membrane cholesterol. Brain Res. 261, 155-158 (1983).

26. Tolbert LM, Lameh, J. Human muscarinic cholinergic receptor Hm1 internalizes via clathrin-



7

coated vesicles. J Biol Chem. 271, 17335-17342 (1996).

27. Scanlon SM, Williams DC, Schloss P. Membrane cholesterol modulates serotonin transporter activity. Biochem. 40, 10507-10513 (2001)

28. Knebl J, DeFazio P, Clearfield MB, et al. Plasma lipids and cholesterol esterification in Alzheimer's disease. Mech Aging Dev. 73, 69-77 (1994).

29. Demeester N, Castro, G, Desrumaux C, et al. Characterization and functional studies of lipoproteins, lipid transfer proteins, and lecithin:cholesterol acyltransferase in CSF of normal individuals and patients with Alzheimer’s disease. J Lipid Res. 41, 963-974 (2000).

30. Koudinov AR, Berezov TT, Koudinova NV. Alzheimer's amyloid beta and lipid metabolism: a missing link? FASEB J. 12, 1097-1099 (1998).

The above article summarises our earlier contribution to the development of the concept of Aβ as an essential normal human apolipoprotein

having certain functions in lipid metabolism

31. Mori T, Paris D, Town T, et al. Cholesterol accumulates in senile plaques of Alzheimer disease patients and in transgenic APPsw mice. J Neuropathol Exp Neurol. 60, 778-785 (2001).

32. Hamanaka H, Katoh-Fukui Y, Suzuki K, et al. Altered cholesterol metabolism in human apolipoprotein E4 knock-in mice. Human Mol Gen. 9, 353-361 (2000).

33. Qiu ZH, Strickland DK, Hyman BT, Rebeck GW. Elevation of LDL receptor-related protein levels via ligand interactions in Alzheimer disease and in vitro. J Neuropath Exp Neurol. 60, 430-440 (2001).

34. Lacko AG, Hayes JD, McConathy WJ, Lacko I, Redheendran R. Lecithin: cholesterol acyl-transferase in Down's syndrome. Clin Chim Acta. 132, 133-141 (1983).

35. Diomede L, Salmona M, Albani D, et al. Alteration of SREBP activation in liver of Trisomy 21 fetuses. Biochem Biophys Res Commun. 260, 499-503 (1999).

36. Refolo LM, Pappolla MA, LaFrancois J, et al. A cholesterol-lowering drug reduces β-amyloid pathology in a transgenic mouse model of Alzheimer's disease. Neurobiol Dis. 8,890-899 (2001).

37. Koudinov AR, Koudinova NV, Berezov TT. Alzheimer's peptides Aβ1-40 and Aβ1-28 inhibit the plasma cholesterol esterification rate. Biochem Mol Biol Inter. 38, 747-752 (1996).

38. Liu Y, Peterson DA, Schubert D. Amyloid beta peptide alters intracellular vesicle trafficking and cholesterol homeostasis. Proc Natl Acad Sci USA. 95, 13266-13271 (1998).

39. Igbavboa U, Avdulov NA, Chochina SV, Sun GY, Wood WG. Amyloid beta peptides and cholesterol dynamics. Neurosci Lett. S55, S25 (2000).

40. Michikawa M, Gong JS, Fan QW, Sawamura N, Yanagisawa K. A novel action of Alzheimer's amyloid beta-protein (Abeta): oligomeric Abeta promotes lipid release. J. Neurosci. 21, 7226-7235 (2001).

41. Yamazaki T, Chang TY, Haass C. Accumulation and aggregation of amyloid beta-protein in late endosomes of Niemann-Pick Type C Cells. J Biol Chem. 276, 4454-4460 (2001).

42. Chochina SV, Avdulov NA, Igbavboa U, Cleary JP, O'Hare EO, Wood WG. Amyloid beta-peptide(1-40) increases neuronal membrane fluidity. Role of cholesterol and brain region. J Lipid Res. 42, 1292-1297 (2001).

43. Muller WE, Kirsch C, Eckert GP. Membrane-disordering effects of beta-amyloid peptides Biochem Soc Trans. 29, 617-623 (2001)

44. Koudinova NV, Koudinov AR, Yavin E. Alzheimer’s Aβ1-40 peptide modulates lipid synthesis in neuronal cultures and intact rat fetal brain under normoxic and oxidative stress conditions. Neurochem Res. 25, 653-660 (2000).

45. Koudinova N, Koudinov AR, Berezov T, Yavin E. Alzheimer's amyloid beta modulates lipid synthesis in rat hippocampus. Soc Neurosci Abst. 25, 1859 (1999).

46. Walters CE, Austen BM. Intracellular cholesterol and β-amyloid as factors in Alzheimer’s disease. Neurobiol Aging. 19, 49S (1998).

47. Manni ME, Cescato R, Paganetti PA. Lack of β-amyloid production in M19 cells deficient in site 2 processing of the sterol regulatory element binding proteins. FEBS Lett. 427, 367-370 (1998).

48. Brion JP, Couck AM, Conreur JL, Octave JN. A phosphorylated tau species is transiently present in developing cortical neurons and is not associated with stable microtubules. In: Kosik KS, Christen Y, Selkoe DJ, eds. Alzheimer’s Disease: Lessons from Cell Biology. Berlin Heidelberg: Springer-Verlag. 150-171 (1995).

49. Taubes G. The soft science of dietary fat. Science. 291, 2536-2545 (2001).

50. Kessler AR, Yehuda S. Learning-induced changes in brain membrane cholesterol and fluidity: implications for brain aging. Int J Neurosci. 28, 73-82 (1985).

51. Grant WB, Clarke RP, Hendrie HC, Hall KS, Gao S, Ogunniyi A. Incidence of Dementia and Alzheimer Disease in Nigeria and the United States. JAMA. 85, 2448-2449 (2001).

52. Kokmen E, Cha RH, Rocca WA. Time trends in the prevalence of dementia and Alzheimer’s disease in Rochester, Minnesota. In: Iqbal K, Swaab DF, Windlad B, Wisniewski HM, eds. Alzheimer's disease and related disorders: etiology, pathogenesis and therapeutics. Chichester:John Wiley and Sons, Ltd. 3-7 (1999).

53. Sparks DL. Intraneuronal beta-amyloid immunoreactivity in the CNS. Neurobiol Aging. 17, 291-299 (1996).

54. Mesulam M-M. Neuroplasticity failure in Alzheimer's disease: bridging the gap between plaques and tangles. Neuron. 24, 521-529 (1999).

55. Zervas M, Dobrenis K, Walkley SU. Neurons in Niemann-Pick disease type C accumulate gangliosides as well as unesterified cholesterol and undergo dendritic and axonal alterations. J Neuropath Exp Neurol. 60, 49-64 (2001).

56. Naslund J, Haroutunian V, Mohs R, et al. Correlation between elevated levels of amyloid β-



8

peptide in the brain and cognitive decline. JAMA. 283, 1571-1577 (2000).

57. Koudinov AR, Koudinova NV, Berezov TT. Is Alzheimer's amyloid plaque formation a condition for neuronal dysfunction? Neurobiol Aging. 21, S155 (2000).

58. Chen G, Chen KS, Knox J, et al. A learning deficit related to age and beta-amyloid plaques in a mouse model of Alzheimer's disease. Nature. 408, 975-979 (2000).

59. Knowles RB, Wyart C, Buldyrev SV, et al. Plaque-induced neurite abnormalities: impli-cations for disruption of neural networks in Alzheimer's disease. Proc Natl Acad Sci USA. 96, 5274-5279 (1999).

60. Kuperstein F, Reiss N, Koudinova NV, Yavin E. Biphasic modulation of protein kinase C and enhanced cell toxicity by amyloid peptide and anoxia in neuronal cultures. J Neurochem. 76, 758-767 (2001).

61. Koudinov A, Groner Y, Segal M. Cu/Zn-SOD transgenic mice are impaired in slow onset, long term potentiation. Neurosci Lett. 51, S23 (1998).

62. Auerbach JM, Segal M. Peroxide modulation of slow onset potentiation in rat hippocampus. J Neurosci. 17, 8695-8701 (1997).

63. Perry G, Nunomura A, Hirai K, Takeda A, Aliev G, Smith MA. Oxidative damage in Alzheimer's disease: the metabolic dimension. Int J Dev Neurosci. 18, 417-421 (2000).

64. Michikawa M, Yanagisawa K. Inhibition of cholesterol production but not of nonsterol isoprenoid products induces neuronal cell death. J Neurochem. 72, 2278-2285 (1999).

65. Zhuo M, Holtzman DM, Li Y, et al. Role of tissue plasminogen activator receptor LRP in hippocampal long-term potentiation. J Neurosci. 20, 542-549 (2000).

66. Champagne D, Rochford J, Poirier J. ApoE and LDL receptor knockout mice display acquisition deficits in the Morris water maze. Soc Neurosci Abstr. 26, 1546 (2000).

67. O'Brien WT, Xu G, Tint GS, Salen G, Servatius RJ. Blocking cholesterol synthesis impairs acquisition of the classically conditioned eyeblink response. Integr Physiol Behav Sci. 35, 120-131 (2000).

68. Xu G, Servatius RJ, Shefer S, et al. Relationship between abnormal cholesterol synthesis and retarded learning in rats. Metabolism Clin Exp. 47, 878-882 (1998).

69. Muldoon MF, Barger SD, Ryan CM, et al. Effects of lovastatin on cognitive function and psychological well-being. Am J Med. 108, 538-546 (2000).

70. Koudinov AR, Koudinova NV. Modulation of cholesterol metabolism initiates Alzheimer’s amyloid deposition and neuronal dysfunction. Soc Neurosci Abstr. 26, 497 (2000).

71. Koudinov AR, Koudinova NV. Neuronal cholesterol pathology is the cause of Alzheimer's disease. Soc Neurosci Abst. 27, 23.3 (2001).

Please note: WEB+ references include more than one citation per reference in web-enhanced article version; selected important article statements are underlined.

Participate in live Participate in live

discussion of the subject of discussion of the subject of cholesterol neurobiologycholesterol neurobiology

and provide

Post Publication Peer-Review for this article at

NetPrintsNetPrintsTMTM article URL:

Consider supportingConsider supporting

Drs. Koudinov researchDrs. Koudinov research

on neurodegeneration.on neurodegeneration.

How?How?

inquire online:inquire online:

http://anzwers.org/free/neurology/

by e.mail:by e.mail:

[email protected]

...or by mail ...or by mail

http://clinmed.netprints.org/cgi/content/full/2001100005v1

BRAIN CHOLESTEROL PATHOLOGY IS THE CAUSE OF …

Documents

Transcript of BRAIN CHOLESTEROL PATHOLOGY IS THE CAUSE OF …