Cell Cycle‐Specific Requirement for Mevalonate, but Not for Cholesterol, for DNA Synthesis in Glial Primary Cultures

Langan, Thomas J.; Volpe, Joseph J.

doi:10.1111/j.1471-4159.1987.tb02894.x

Cited by 54 publications

(48 citation statements)

References 60 publications

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“…A recent study has shown that statins cause intracellular accumulation of A␤ via a non-steroidal isoprenoid-dependent mechanism (67). In our study, however, we added mevalonate to avoid toxicity due to inhibition of these non-steroidal pathways (51,52,54).…”

Section: Discussionmentioning

confidence: 96%

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Independent Inhibition of Alzheimer Disease β- and γ-Secretase Cleavage by Lowered Cholesterol Levels

Grimm

Tomic

et al. 2008

Journal of Biological Chemistry

120

107

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The major molecular risk factor for Alzheimer disease so far identified is the amyloidogenic peptide A␤ 42 . In addition, growing evidence suggests a role of cholesterol in Alzheimer disease pathology and A␤ generation. However, the cellular mechanism of lipid-dependent A␤ production remains unclear. Here we describe that the two enzymatic activities responsible for A␤ production, ␤-secretase and ␥-secretase, are inhibited in parallel by cholesterol reduction. Importantly, our data indicate that cholesterol depletion within the cellular context inhibits both secretases additively and independently from each other. This is unexpected because the ␤-secretase ␤-site amyloid precursor protein cleaving enzyme and the presenilin-containing ␥-secretase complex are structurally different from each other, and these enzymes are apparently located in different subcellular compartments. The parallel and additive inhibition has obvious consequences for therapeutic research and may indicate an intrinsic cross-talk between Alzheimer disease-related amyloid precursor protein processing, amyloid precursor protein function, and lipid biology.A␤ peptides are the main proteinaceous component of Alzheimer disease amyloid plaques. A␤ is derived from posttranslational cleavage of the amyloid precursor protein (APP). Cleavage of APP by BACE I (1) at the N terminus of the A␤ sequence generates a C-terminal fragment (C99) that includes the entire A␤ sequence. In mouse cortical neurons BACE I is essential for APP ␤-cleavage (2). A second proteolytic activity termed ␥-secretase cleaves APP at the C-terminal end of the A␤ sequence, releasing A␤ 40 and A␤ 42 during normal cellular metabolism of APP (3, 4). A fraction of APP is processed by the ␣-secretase pathway in which APP is cleaved within the A␤ region thus precluding A␤ formation. However, neurons predominately use the ␤-secretory pathway at the expense of the ␣-secretory pathway to process APP (5). Moreover, neurons produce significant amounts of intracellular A␤ in vivo and in vitro (6 -8). A specific feature of ␥-secretase is that it is capable of cleaving APP only after a major part of the APP luminal domain is removed. Under normal circumstances it is therefore not possible to assay ␥-secretase activity directly.Analyses of APP-FAD mutations (9) as well as of PS-FAD mutations (10) have corroborated the assumption that a small increase in A␤ 42 levels causes AD (11). The subcellular activities of both ␤-and ␥-secretase have been extensively studied. Processing of APP to A␤ differs for different intracellular compartments (12) and depends among others on the interaction of membrane composition and the APP transmembrane domain (13). Variable amounts of ␤-secretase activity were found along the secretory pathway starting in the ER/intermediate compartment, post-Golgi vesicles, TGN, and endosomes (14, 15). In contrast, ␥-secretase activity was found to be prominent in the ER, TGN, and plasma membrane and to produce different A␤ isoforms in different compartments (reviewed by Hartmann (...

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Section: Discussionmentioning

confidence: 96%

“…De novo cholesterol synthesis was inhibited by lovastatin, an inhibitor of HMG-CoA reductase. A basic level of mevalonate was maintained by adding mevalonate to the cell culture media to avoid toxicity due to inhibition of non-steroidal pathways (51,52). Plasma membrane cholesterol was extracted by methyl-␤-cyclodextrin.…”

Section: Methodsmentioning

confidence: 99%

Independent Inhibition of Alzheimer Disease β- and γ-Secretase Cleavage by Lowered Cholesterol Levels

Grimm

Tomic

et al. 2008

Journal of Biological Chemistry

120

107

View full text Add to dashboard Cite

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“…First, de novo synthesis of cholesterol was inhibited by lovastatin or simvastatin. Biochemical pathways for nonsteroidal products were allowed to proceed by supplementing cells with mevalonate in the culture medium (33,34). Second, plasma membrane cholesterol was extracted by CDX, which is very efficient in selectively and rapidly extracting cholesterol from the plasma membrane (35).…”

Section: Resultsmentioning

confidence: 99%

Simvastatin strongly reduces levels of Alzheimer's disease β-amyloid peptides Aβ42 and Aβ40 in vitro and in vivo

Faßbender

Simons

Bergmann

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

1,042

724

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Recent epidemiological studies show a strong reduction in the incidence of Alzheimer's disease in patients treated with cholesterol-lowering statins. Moreover, elevated A␤42 levels and the 4 allele of the lipid-carrier apolipoprotein E are regarded as risk factors for sporadic and familial Alzheimer's disease. Here we demonstrate that the widely used cholesterol-lowering drugs simvastatin and lovastatin reduce intracellular and extracellular levels of A␤42 and A␤40 peptides in primary cultures of hippocampal neurons and mixed cortical neurons. Likewise, guinea pigs treated with high doses of simvastatin showed a strong and reversible reduction of cerebral A␤42 and A␤40 levels in the cerebrospinal fluid and brain homogenate. These results suggest that lipids are playing an important role in the development of Alzheimer's disease. Lowered levels of A␤42 may provide the mechanism for the observed reduced incidence of dementia in statin-treated patients and may open up avenues for therapeutic interventions.A part from age, environmental factors have only slight influence on the incidence of Alzheimer's disease (AD). Very recently, two independent reports showed a strong decrease in the incidence of AD and dementia for patients that were treated with statins (1, 2). Both studies were retrospective, and statins were not given in any relation to dementia. Usually statins are prescribed for treatment of elevated serum cholesterol levels in patients. They reduce cholesterol levels by inhibiting the bottleneck enzyme of cholesterol synthesis, 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase. They are widely used drugs, well characterized and considered to be very safe for long-time treatment, and approved for use in elderly patients (3, 4).The 4 allele of the apolipoprotein E (apoE) is the major genetic risk factor for AD (5). Several lines of evidence indicate that apoE 4 and statins have a related influence on AD. The normal cellular function of apoE is uptake and delivery of lipids. The isoform apoE 4 correlates with an increased risk for atherosclerosis (6) and amyloid plaque formation (7). Moreover, elevated cholesterol uptake increases amyloid plaque formation or amyloid deposition (8,9). This correlation may be extended to A␤ production, since cellular cholesterol levels affect neuronal A␤ production in vitro (10). Initially, A␤ has been a focus of AD research, because it was found to be the major constituent of the amyloid plaque. It is unknown whether the amyloid plaque is actively involved in the neurodegenerative process in AD or instead is a consequence of the disease process. More recently, however, A␤ has been a focus of AD research not because of it presence in the amyloid plaque, but because an overproduction of a minor A␤ isoform, A␤42, is linked to all identified inherited forms of AD (11-13).A␤ is produced during normal cellular processing of the Alzheimer amyloid precursor protein (APP) (14) by ␤-secretase and ␥-secretase (15). While the majority of all A␤ isoforms produced is A␤40, Ϸ10% of total A␤ ...

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“…Lovastatin and simvastatin are known to reversibly arrest the cell cycle progression of mammalian cells in the G, phase with drug concentrations ranging from 1 to 10 pug -ml -for human bladder carcinoma T24 cells (11) and human fibroblasts (15) to 60 ,ug -ml-1 for rat brain glial cells (14). Blocked cells are viable, and cytostatic effects can be reversed by the addition of exogenous mevalonate, the product of the HMG-CoA reductase reaction.…”

Section: Discussionmentioning

confidence: 99%

“…After the 30th hour, corresponding to the beginning of the schizont stage, the inhibition of growth was weak or totally absent. Lovastatin and simvastatin are known to act as competitive inhibitors of HMG-CoA reductase and to block the proliferation of eukaryotic cells in the GI phase (11,14,15). For example, treated human bladder carcinoma T24 cells are viable for up to 72 h and are able to enter into the S phase after removal of the drug (11).…”

Section: Methodsmentioning

confidence: 99%

3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors lovastatin and simvastatin inhibit in vitro development of Plasmodium falciparum and Babesia divergens in human erythrocytes

Grellier

Valentin

Millerioux

et al. 1994

Antimicrob Agents Chemother

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The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors lovastatin and simvastatin inhibit the in vitro intraerythrocytic development of Plasmodium falciparum and Babesia divergens, with concentrations inhibiting parasite growth by 50% in the ranges of 10 to 20 and 5 to 10 ug -ml-', respectively. For P.falciparum, the 50% inhibitory concentrations were in the same range whatever the chloroquine susceptibility of the strains tested (strain F32/Tanzania [chloroquine susceptible] or FcB.1/Columbia [resistant]). The stage-dependent susceptibility of P. falciparum to simvastatin was studied by subjecting synchronized cultures to 6-h pulses of drug throughout the 48-h erythrocytic life cycle. The most important inhibitory effects were observed between the 12th and 30th hours of the cycle, corresponding to the trophozoite stage. This period precedes the S phase and the nuclear divisions. Parasites in the newly formed ring stage (time zero to the 6th hour of the cycle) and the schizont stage (30th to 48th hour of the cycle) were weakly or not susceptible to simvastatin pulses.The Apicomplexa hemoparasites Plasmodium falciparum and Babesia divergens, the causative agents of human malaria and bovine babesiosis, respectively, still constitute major health and economic problems in most developing countries (12,24). The (8,21,22) and depend on their import from the host's plasma. With the use of a serum-free medium, we have recently found a unidirectional transfer of phospholipids from human high-density lipoproteins to the intraerythrocytic P. falciparum by ducts and vesicles moving from the erythrocyte to the parasitophorous vacuole membranes (6). A similar phospholipid transfer was observed in B. divergensinfected erythrocytes (RBC), but no ducts or vesicles were observed (21). High-density lipoproteins support the in vitro growth of B. divergens and P. falciparum in the absence of other major serum components and appeared to be a lipid source for the parasites (6,7,21 by P. falciparum-infected RBC, we have shown evidence for an isoprenoid metabolisnm until, at least, the farnesyl PPi step (16).This pathway, with numerous end products, is essential for various cellular functions such as mitochondrial electron transport, tRNA synthesis, control of cell growth, protein glycosylation, and intracellular targeting (4). In both prokaryotic and eukaryotic cells, the isoprenoid pathway is highly regulated through feedback regulations at the level of two sequential enzymes involved in the synthesis of mevalonate: 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) synthase and HMGCoA reductase (4). HMG-CoA reductase inhibitors are available as hypocholesterolemic agents in humans. The goal of our study was to establish whether the HMG-CoA reductase inhibitors lovastatin and simvastatin are able to inhibit the in vitro development of P. falciparum and B. divergens. MATERIALS AND METHODSLovastatin and simvastatin, both in the lactone form, were kindly provided by J. C. Mazi&re (Hopital St-Antoine, Paris, France) and by C. Fous...

show abstract

Cell Cycle‐Specific Requirement for Mevalonate, but Not for Cholesterol, for DNA Synthesis in Glial Primary Cultures

Cited by 54 publications

References 60 publications

Independent Inhibition of Alzheimer Disease β- and γ-Secretase Cleavage by Lowered Cholesterol Levels

Independent Inhibition of Alzheimer Disease β- and γ-Secretase Cleavage by Lowered Cholesterol Levels

Simvastatin strongly reduces levels of Alzheimer's disease β-amyloid peptides Aβ42 and Aβ40 in vitro and in vivo

3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors lovastatin and simvastatin inhibit in vitro development of Plasmodium falciparum and Babesia divergens in human erythrocytes

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