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clinmed/2001100005v1 (November 27, 2001)
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Copyright © 2001 Alexei Koudinov and Natalia Koudinova
BRAIN CHOLESTEROL PATHOLOGY IS THE CAUSE OF ALZHEIMER’S DISEASE
Alexei R. Koudinova,CA and Natalia V. Koudinovaa,b
a Berezov Academic Laboratory, Russian Academy of Medical
Sciences, Timoshenko St., 38-27, Moscow, 121359 Russia;
b Weizmann Institute of Science, Department of Biological Regulation, Rehovot, 76100 Israel.
First submitted: January 5, 2001, Published online: November, 2001
CLINICAL AND EXPERIMENTAL STATE OF THE ART
FIGURE 1: AN EXPERIMENTAL EVIDENCE
CHOLESTEROL, SYNAPTIC FUNCTION AND ALZHEIMER’S DISEASE
CHOLESTEROL AND AMYLOID BETA PROTEIN
In accord with the above papers [ 6, 7 ] and despite of tolerating hypercholesterolemia [ 12 ] albino wistar rats fed a cholesterol diet demonstrate increased cholesterol and phospholipid synthesis in the hippocampus (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 dynamics [ 11, 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 synthesis [ 17 ] 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, Table) and associated turnover upregulation [ 18 ].
The experimental condition of increased cholesterol efflux is also characterized by paired helical filaments (PHF)-tau hyperphosphorylation in neurofibrillary tangles (NFT) and neurite degeneration [ 11 ], another key histochemical feature of AD. The observation of cholesterol-dependent tau phosphorylation in ex-vivo hippocampal slices [ 11 ] 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 rabbits [ 7 ] suggest that NFT formation is a secondary phenomenon of abnormal neuronal cholesterol homeostasis [ LE1 ].
Consistent with previous data [ 8, 10, 12, 13, 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. 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 Ab with 4G8 (1:1000) monoclonal antibody [ 11 ] (anti-rodent/humanAb17-24) in brain sections of cholesterol fed rats (B, C, E). Alzheimer's-like plaque amyloid (B, C) and vascular Ab 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 mM for panels A-C; and 30 mM for panels D, E.
Panel F demonstrates impairment of tetanus induced long term potentiation (LTP) in CA1 of ex-vivo hippocampal 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 pathology lacking Ab deposition (that we reported recently in The FASEB Journal [ 11 ] indicates that cholesterol (and not Ab) misregulation is a primary cause of synaptic dysfunction. Moreover, as lipid metabolism functional player, Ab likely modulates its biology in presented here chronic model of cholesterol-fed rat in order to recover impaired rat brain cholesterol homeostasis (see below).
CHOLESTEROL, SYNAPTIC FUNCTION AND ALZHEIMER’S DISEASE
Conceivable, 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 functione and cause Alzheimer’s-like neurodegeneration features (Fig. 1 and Scheme 1) [ 6, 8, 11, 15, 17, 25, 26, 27WEB+ ]. Importantly, crosstalk of hepatic and neuronal cholesterol (see previously and [ 10, 12, 13, 14 ]) 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, 29, 30 ] implying an abnormal CSF high density lipoprotein interconversion, 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 e4/e4 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 e4/e4 subjects. Fifth, recent observation documented significant elevation of the LDL receptor related protein [ LE2 ] levels in AD frontal cortex [ 33 ] 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.
CHOLESTEROL AND AMYLOID BETA PROTEIN
The biochemical relation of cholesterol and Ab, however, is bidirectional, and the modulation of neuronal cholesterol dynamics by Ab likely has important functional consequences.
Particularly, Ab 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 ] Ab also modulates neuronal physical property of membrane fluidity [ 42, 43 ] suggested to be important for cholesterol-dependent cell receptor machinery impairment (discussed in Ref. 11). Additionally, Ab 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 lowering [ 46 ]) 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, 45, 46 ]. The latter results highlight the importance of developmental, tissue and neuronal functional specificity of Ab-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, 45 ]. These data also suggest that Ab 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, 13, 14 ]. Taken together, the above functional consideration and recent data on the importance of cholesterol compartmentation for Ab generation [ 2, 41 ] indicate feedback functional relation between cholesterol and Ab homeostasis, additionally supported by a dependency of amyloid precursor protein processing and Ab production on the site 2 processing of SREBP [ 47 ] (the major regulatory protein in cholesterol metabolism [ 21WEB+, 24, 35]) and associated inability of cells to upregulate the expression of several enzymes and proteins involved in cholesterol synthesis and turnover [ 47 ].
We believe that the fundamental pathophysiological
event in most common sporadic forms of AD is accurate brain cholesterol
( See Scheme 1 )
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LETTERS TO EDITOR
[ Authors "eLetters to Editor" collection ]
LE1. Koudinov AR, Koudinova NV. Alzheimer's pathogenesis: tau and amyloid - a consensus or a challenge for a third party quest ? Br Med J. E.letter published online September 4, 2001 [ Read the letter ].
LE2. Koudinov AR, Koudinova NV. LRP: a cholesterol recruitment checkpoint for neuronal structure-functional plasticity? J Clin Invest. E.letter published online October 12, 2001 [ Read the letter ].
LE3. Koudinov AR, Koudinova NV. Cholesterol, synaptic function and Alzheimer's disease. Br Med J. E.letter published online October 16, 2001 [ Read the letter ].
LE4. Koudinov AR, Berezov TT, Koudinova NV. Beware: the link is not simple. Neurology E.letter published online October 16, 2001 [ Read the letter ].
LE5. Koudinov AR, Koudinova NV. Dementia, cholesterol and the soft science of dietary fat. Br Med J. E.letter published online July 27, 2001 [ Read the letter ].
LE6. Koudinov AR. Pioneering new era of biomedical science publishing. Br Med J. E.letter published online October 8, 2001 [ Read the letter ].
LE7. Koudinov AR, Koudinova NV. (2001) Looking forward for a historic issue, or: Is there anything besides amyloid? Br Med J. E.letter published online October 19, 2001 [ Read the letter ].
LE8. Koudinov AR, Koudinova NV. (2001) Cholesterol supply and synaptic plasticity. Submitted to Science on November 9, 2001 [ Read the letter ].
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