The density profile and cholesterol concentration of serum lipoproteins in domestic and laboratory animals

Terpstra, A.H.M.; Sánchez‐Muniz, Francisco J.; West, C.E.; Woodward, Christopher J. H.

doi:10.1016/0305-0491(82)90479-5

Cited by 41 publications

(44 citation statements)

References 24 publications

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“…Furthermore, recovery of initial A␤ levels can be monitored easily after drug removal. Importantly, guinea pigs are well-established animals for lipid physiology studies as they offer several advantages over the use of mice because they are more closely related to the human situation (38)(39)(40)(41). Unlike mice or rats, guinea pigs have the human A␤ sequence.…”

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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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

View full text Add to dashboard Cite

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“…Thus, comparing results of studies on cholesterol metabolism from mice, guinea pigs, and humans has limitations. For instance, in wild-type mice, plasma levels of cholesterol are relatively low, and cholesterol is predominantly found in the high-density lipoprotein fraction (Terpstra et al, 1982), whereas in humans, most cholesterol is located in the LDL fraction (Fielding and Fielding, 1982).…”

Section: Discussionmentioning

confidence: 99%

Brain Cholesterol Synthesis in Mice Is Affected by High Dose of Simvastatin but Not of Pravastatin

Thelen

Rentsch

Gutteck

et al. 2006

The Journal of Pharmacology and Experimental Therapeutics

135

122

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On a global scale, there is an increasing tendency for a more aggressive treatment of hypercholesterolemia. Minor effects of statins on brain cholesterol metabolism have been reported in some in vivo animal studies, and it seems that this is due to a local effect of the drug. We treated male mice of the inbred strain C57/BL6 with a high daily dose of lipophilic simvastatin (100 mg/kg b.wt.) or hydrophilic pravastatin (200 mg/kg b.wt.) or vehicle (controls) by oral gavage for 3 days. To compare the impact of both statins on brain cholesterol synthesis and degradation, levels of cholesterol, its precursor lathosterol, and its brain metabolite 24(S)-hydroxycholesterol as well as statin concentrations were determined in whole-brain lipid extracts using mass spectrometry. The expression of 3-hydroxy-3-methylglutaryl (HMG)-coenzyme A (CoA) reductase mRNA and of other target genes were evaluated using real-time reverse transcription-polymerase chain reaction. In addition, analysis of liver and serum samples was performed. Similar levels of simvastatin and pravastatin were detected in whole-brain homogenates. Cholesterol contents in the brain, liver, and serum were not affected by high-dose statin treatment. Whereas brain cholesterol precursor levels were reduced in simvastatin-treated animals only, no effect was observed on the formation of the brain cholesterol metabolite, 24(S)-hydroxycholesterol. Polymerase chain reaction analysis revealed that mRNA expression of HMG-CoA reductase and ATP-binding cassette transporter A1 in the brain was significantly up-regulated in simvastatintreated animals compared with pravastatin-treated or control animals. We conclude that, under the present experimental conditions, brain cholesterol synthesis is significantly affected by short-term treatment with high doses of lipophilic simvastatin, whereas whole-brain cholesterol turnover is not disturbed.

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“…After ultracentrifugation, the lipoprotein bands are visible in the gradient and can be photographed. We have used this method in order to compare the lipoprotein profiles in the sera of various experimental and domestic animals (Terpstra et al, 1982a). Further, we have studied the effects of the type and proportion of dietary casein and soybean protein on the serum lipoprotein pattern in several animal species, such as rabbits, rats, chickens and guinea-pigs (Terpstra et al, 1982b(Terpstra et al, , 1983aMol et al, 1982;West et al, 1983).…”

Section: Methodsmentioning

confidence: 99%

Density profile and cholesterol concentration of serum lipoproteins in experimental animals and human subjects on hypercholesterolaemic diets

Terpstra

Beynen

1984

Comparative Biochemistry and Physiology Part B: Comparative Bio

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Abstract--l. The density profile of Sudan black stained serum lipoproteins was studied in human subjects and various animal species on diets supplemented with cholesterol.2. In the animals studied (rabbits, calves, mice, chickens, rats and guinea-pigs), the feeding of cholesterol resulted in an elevation of serum cholesterol levels together with marked changes in the density profile and the cholesterol concentration of the serum lipoproteins. Large differences between animal species in their response to dietary cholesterol were found.3. In a human subject, an increased concentration of serum cholesterol due to the consumption of a diet supplemented with six egg yolks per day was reflected in an elevated level of LDL cholesterol, while changes in the density profile of stained serum lipoproteins were not observed.4. In subjects with familial type IlI and type IV hyperlipoproteinaemia, marked differences in the density profile of lipoproteins were found when compared with that of normolipoproteinaemic subjects.5. The density profile of stained iipoproteins in the type Ill patients was remarkably similar to that in cholesterol-fed chickens and lean Zucker rats.

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The density profile and cholesterol concentration of serum lipoproteins in domestic and laboratory animals

Cited by 41 publications

References 24 publications

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

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

Brain Cholesterol Synthesis in Mice Is Affected by High Dose of Simvastatin but Not of Pravastatin

Density profile and cholesterol concentration of serum lipoproteins in experimental animals and human subjects on hypercholesterolaemic diets

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