Skip Navigation

This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Search for citing articles in:
ISI Web of Science (52)
Right arrowRequest Permissions
Google Scholar
Right arrow Articles by Lambert, J. C.
Right arrow Articles by Chartier-Harlin, M. C.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Lambert, J. C.
Right arrow Articles by Chartier-Harlin, M. C.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

Human Molecular Genetics Pages 2151-2154  

Distortion of allelic expression of apolipoprotein E in Alzheimer's disease
Introduction
Results
Discussion
Materials And Methods
   RNA extraction
   RT-PCR amplification of APOE mRNAs
   Electrophoresis
   Silver staining
   Allele quantitation
References

Distortion of allelic expression of apolipoprotein E in Alzheimer's disease

Distortion of allelic expression of apolipoprotein E in Alzheimer's disease

Jean-Charles Lambert1,2, Jordi Pérez-Tur1,3, Marie-Joëlle Dupire1, Douglas Galasko4, David Mann5, Philippe Amouyel2, John Hardy3, André Delacourte1, Marie-Christine Chartier-Harlin1,2,*

1INSERM Unité 422, Place de Verdun, 59045 Lille Cedex, France, 2INSERM CJF95-05, Institut Pasteur de Lille, 1 rue de Calmette, 59019 Lille Cedex, France, 3Birdsall Building, Mayo Clinic Jacksonville, 4500 San Pablo Road, Jacksonville, FL 32224, USA, 4UCSD, Medical Centre, Pulman Ambulatory Care Centre, 9350 Campus Point Drive, La Jolla, CA 92037, USA and 5Department of Pathological Sciences, Stopford Building, University of Manchester, Oxford Road, Manchester M13 9PT, UK

Received July 25, 1997; Revised and Accepted August 2, 1997

The APOE [epsis]4 allele is a strong genetic susceptibility factor for Alzheimer's disease. Interaction with other biological factors may modulate the effect of the apoE isoforms. However, previous work suggested that other genetic variability within the APOE locus, influencing the effect of the [epsis]4 allele, may exist. Such variability could modify the expression of the APOE gene and, in particular, the level of expression of APOE alleles could be an important determinant of disease pathogenesis. To test this hypothesis we examined the levels of expression of APOE in heterozygotes with AD and in controls, using a new method of semi-quantitation. We report that relative [epsis]4 mRNA expression is increased in AD compared with controls and suggest that genetic variability in the neural expression of APOE contributes to disease risk.

INTRODUCTION

The [epsis]4 allele of the APOE gene is a major risk factor for late-onset Alzheimer's disease (LOAD) (1), and is also implicated as a risk factor for early-onset disease in some populations (2,3). Previous studies have described [epsis]4 homozygotes as having a higher risk of developing disease than [epsis]3[epsis]4 heterozygotes. However, individuals bearing one or two [epsis]4 alleles, do not inevitably develop the disease. Detailed genetic analysis around the APOE locus has suggested the existence of other genetic variability in this region which could contribute to disease risk (4). There are two possible explanations for these observations: (i) there is another genetically variable locus in the vicinity of the APOE gene involved in the pathogenesis of the disease; (ii) there is a genetic variability in the control of expression of the APOE gene (4).

There has been little examination of the mRNA expression of APOE in AD (5,6). The available evidence suggests that APOE expression is increased by neuronal damage (7,8) and that the bulk of the expression occurs in astrocytes (5). This expression is believed to be part of a compensatory mechanism aimed at aiding reafferentation and reactive synaptogenesis (9). Only a few studies have examined the expression of the apoE protein in AD cases and controls relative to the APOE genotype (9,10). Bertrand et al. have suggested that the amount of apoE protein could be inversely correlated to the number of [epsis]4 alleles carried by subjects: higher levels were observed in [epsis]3 homozygotes, lower in [epsis]4 homozygotes and intermediate levels in [epsis]3[epsis]4 heterozygotes (10).

We hypothesised that, since [epsis]4 homozygotes have a higher risk of developing disease than [epsis]3[epsis]4 heterozygotes, and a high proportion of individuals with the latter genotype reach a greater age without developing AD, a likely explanation of this was that there was genetic variability in neural expression at the APOE locus and that [epsis]3[epsis]4 heterozygote individuals who were high [epsis]4 expressors and/or low [epsis]3 expressors were more likely to develop AD than individuals with high [epsis]3 expressors and/or low [epsis]4 expressors.

The identification of the APOE allele transcription products is easily achieved by RT-PCR, using restriction fragment length polymorphism. We developed a semi-quantitative assay to measure allelic expression of APOE mRNA by RT-PCR using silver staining (11). This method of quantitation has been applied to brains of heterozygote subjects collected at various centres and used to assess the percentage of [epsis]4 mRNA expression in [epsis]3[epsis]4 and [epsis]2[epsis]4 subjects and [epsis]2 mRNA expression in [epsis]2[epsis]3 individuals. This has been carried out both in AD cases and controls.

RESULTS

We selected a series of [epsis]3[epsis]4, [epsis]2[epsis]4, [epsis]2[epsis]3 AD cases (n = 14) and controls (n = 12) in order to measure the relative level of expression of the APOE allele in the frontal cortex (Fig. 1). We observed that [epsis]3 mRNA expression was consistently greater than [epsis]4 mRNA expression in all cases (Fig. 2). In addition, there was a clear and consistent difference in the [epsis]4 allelic expression ratio between AD cases and controls (Fig. 2), with AD cases showing a higher relative expression of [epsis]4 mRNA than controls (34.4 ± 2.6% versus 22.6 ± 1.8%, respectively, P = 0.001 with Mann-Whitney test). Regarding the other heterozygous genotypes, the small size of each group prevented us from reaching any definite conclusion. Nevertheless, a trend towards the same situation as observed in the [epsis]3[epsis]4 group could be noted, an increase in the expression of the [epsis]4 allele in the [epsis]2[epsis]4 group (42.6 ± 3.7% in the AD cases versus 28.9 ± 1.2% in the only control), whereas nothing was apparent in the [epsis]2[epsis]3 group (39.0 ± 1.4% in the only AD case versus 45.8 ± 4.3% in controls). Furthermore, a difference in the allelic expression ratio between [epsis]2[epsis]4 and [epsis]3[epsis]4 AD cases was observed, since [epsis]2[epsis]4 patients showed a 1.25-fold increase of the [epsis]4 allele ratio (P = 0.01 with Mann-Whitney test).


Figure 1 Semi-quantitation of the [epsis]4 allele ratio in a control case. The final [epsis]4 allele ratio calculated from this data was 21.42%.


Figure 2 Differential expression of the APOE mRNA for the three heterozygote genotypes in Alzheimer's disease cases and controls. The [epsis]2 mRNA percentage was measured in the [epsis]2[epsis]3 population and the [epsis]4 mRNA percentage in the [epsis]3[epsis]4 and [epsis]2[epsis]4 population. The average level of expression is indicated by a bold line in each category. For each brain sample, RT-PCR and semi-quantitation was repeated three times.

DISCUSSION

It is important to note that measurement of the ratio of expression of the two alleles in heterozygotes is likely to be a much more robust measurement than the determination of absolute levels of mRNA expression in the same tissue, since the latter will be profoundly affected by post-mortem delay, agonal state and cell population and density.

As can be seen in Figure 2, the level of expression of the [epsis]3 allele is consistently higher than that of the [epsis]4 allele in the AD group as well as in the control group. These data suggest that there is either differential stability of the different mRNA species, or that there is genetic variability in the expression of the two alleles in disequilibrium with the coding polymorphism. However, in addition there was a clear and consistent difference in the [epsis]4 allelic expression ratio between AD cases and controls. These results are consistent with the notion that part, at least, of the genetic risk of developing AD encoded at the APOE locus relates to the expression of this protein in the brain. It would seem that heterozygote individuals who express a relatively high proportion of the [epsis]4 allele are at greater risk for developing disease than those expressing a relatively low proportion. The observation that the different alleles of APOE are not equally expressed may be of importance in the formulation of hypotheses relating to the role of APOE in the pathogenesis of AD in general. At present, there is much speculation and experimentation designed to determine the nature of the role of the different alleles of APOE in the pathogenesis of AD. As previously suggested, the E4 isoform may facilitate (12) or not limit (13) the amyloid substance deposition. This isoform would not protect against oxidative stress, conversely to the E2 isoform (14). Finally, it has been suggested that the E2 and E3 isoforms may prevent the aggregation of Tau protein, while the E4 isoform may not prevent the paired helical filament formation (15). However, these hypotheses are based on the premise that the APOE allele isoforms are equally expressed and present at similar concentrations in the brain. These isoform-specific differences could be enhanced by a different representation of each isoform in an individual.

To date, it seems difficult to link APOE mRNA and apoE protein levels. Several studies had explored this issue reporting contradictory findings in brain (10,16), cerebrospinal fluid (17,18) and plasma (19). But even if the apoE level was tested according to the APOE genotype, none of the previous studies have been able to determine the relative ratio between the different isoforms and thus our results are not comparable with them. The development of isoform-specific monoclonal antibodies would help to determine whether the variation that is observed in our population is also present at the protein level (20).

There are two major findings in our work. First, that the expression of the [epsis]3 allele is consistently higher than the expression of the [epsis]4 allele. Second, that the expression of the [epsis]4 allele beyond a certain level seems to greatly influence the vulnerability of an individual to Alzheimer's disease.

It is interesting to note that APOE is up-regulated as a consequence of an insult. Poirier et al. showed an increase in the level of expression of APOE mRNA in rat after lesioning of the cerebral cortex (6). Similarly, Diedrich et al. showed that APOE mRNA was increased in AD brains (5). Together these results support an event, which may lead to an increase of the APOE mRNA and, in parallel, a distortion of the allelic expression. The distortion of the allelic expression may be specific to brain, and possibly restricted to certain areas (21). This suggests a neural genetic susceptibility for AD associated with the APOE gene.

Interestingly, Templeton reached a similar conclusion using a cladistic analysis of our previously reported genetic data (4). Using haplotype data from markers surrounding the APOE locus, including the APOE polymorphism, Templeton showed that the coding polymorphism in the APOE gene was not sufficient to explain the increased risk for AD (22). Our data suggest that the influence of non-coding polymorphism on ApoE expression may supply the rest of the answer.

MATERIALS AND METHODS

RNA extraction

Fourteen late-onset AD cases of Caucasian origin with a mean age of 74.1 ± 11.8 years (five male and nine female) and 12 controls with a mean age of 83.0 ± 10.6 years (five male and seven female) were selected as a function of their APOE genotype (23). The mean age at sampling was 75.6 ± 8.8 years for the AD cases genotyped [epsis]3[epsis]4 and 77.6 ± 11.0 years for the controls genotyped [epsis]3[epsis]4. Diagnoses were confirmed by neuropathological examination.

Total RNA extraction was performed from frontal lobe samples as described by Gilmour et al. (24) and then digested by DNase (Eurogentec). No DNA contamination was observed after DNase digestion as detected by PCR of the digested product.

RT-PCR amplification of APOE mRNAs

The RT reaction was performed for 1 h 30 min at 37°C, using the F4 primer 5[prime]-ACAGAATTCGCCCCGGCCTGGTA-3[prime] at 50 pmol and 1 [mu]g of total RNA as template for the M-MLV reverse transcriptase following the conditions described by the supplier (Gibco/BRL). The PCR step was carried out with the F6 primer 5[prime]-TAAGCTTGGCACGGCTGTCCAAGGA-3[prime] at 50 pmol in a final volume of 10 [mu]l, for 30 cycles (1 min at 94°C, 1 min at 58°C and 1 min at 72°C each cycle) to remain in the linear range of the reaction. Briefly, PCR was performed in a total volume of 25 [mu]l containing 1.25 U Taq DNA polymerase, 0.2 mM of each dNTP, 4 mM of DTT, 0.1 mM of MgCl2, 0.04% of Triton X-100, 10% (v/v) of glycerol using the whole RT reaction as template.

Electrophoresis

RT-PCR DNA was then digested by 12 U CfoI endonuclease (Promega), DNA fragments were resolved on an 8% polyacrylamide gel (acrylamide:bisacrylamide 19:1), over 4 h at 12 V/cm. A range from 6 to 0.2 [mu]l of the RT-PCR product was loaded.

Silver staining

The gel was fixed over 90 min in 10% (v/v) ethanol, 0.5% (v/v) acetic acid. After two washings with deionised water, the gel was placed in silver nitrate solution (1 mg/ml) for 25 min. The gel was then washed twice with deionised water. The DNA polymorphism fragments were stained for 30 min in 0.037 % formaldehyde (v/v), hydroxyde nitrate (15 mg/ml). Finally, the reaction was stopped in a sodium carbonate solution (15 mg/ml). The developer and silver nitrate solutions were prepared extemporaneously. The gel was digitalised on a Sharp JX-325 high resolution colour scanner, and the fragment intensity was measured using the Image Master Software (Pharmacia) with appropriate background subtract.

Allele quantitation

The percentage of the [epsis]4 allele was calculated with the equation below as described in ref. 11:
No[epsis]4 mRNA and No[epsis]3 mRNA were the initial number of the [epsis]3 and [epsis]4 mRNAs. [alpha][prime][epsis]4 mRNA and [alpha][prime][epsis]2 or [epsis]3 mRNA were the coefficients allowing silver staining, and the phenomenon of saturation due to this staining, to be integrated and normalised. A is a coefficient of proportionality, correcting for the length difference between each restriction fragments. After digestion by CfoI, the [epsis]3, [epsis]2 and [epsis]4 alleles can be characterised by 91, 83 and 72 bp fragments, respectively. The A coefficient is therefore calculated as A = 91/72 for [epsis]3[epsis]4 individuals, A = 83/72 for [epsis]2[epsis]4 individuals and A = 91/83 for the [epsis]2[epsis]3 population.

Because both [epsis]2 and [epsis]3 alleles give a restriction length fragment at 91 bp, AOD[epsis]2 mRNA + OD[epsis]3 mRNA = OD91 bp.

The initial [epsis]2 allele percentage in the [epsis]2[epsis]3 population was calculated as:

Details of the calculations and modelling of the method are described in ref. 11. We tested the viability of this approach on the APOE alleles by using genomic DNA as template for different parameters such as initial concentrations of DNA template or initial percentage of an allele compared with another (11).

Linear regressions (necessary to perform ratio percentage) and Mann-Whitney U-test were performed using SAS software release 6.04 (SAS Institute Inc., Cary, NC, USA).

REFERENCES

1. Saunders, A.M., Strittmatter, W.J., Schmechel, D., St. George-Hyslop, P.H., Pericak-Vance, M.A., Joo, S.H., Rosi, B.L., Gusella, J.F., Crapper-MacLachlan, D.R., Alberts, M.J., Hulette, C., Crain, B., Goldgaber, D. and Roses, A.D. (1993) Association of apolipoprotein E allele [epsis]4 with late-onset familial and sporadic Alzheimer's disease. Neurology, 43, 1467-1472. MEDLINE Abstract

2. Van Duijn, C.M., De Kniff, P., Wehnert, A., De Voecht, J., Bronzova, J.B., Havekes, L.M., Hofman, A. and Van Broeckhoven, C. (1995) Reduced survival of patients with early-onset Alzheimer's disease that carry the Apolipoprotein [Egr]2 allele. Ann. Neurol., 37, 605-610. MEDLINE Abstract

3. Pérez-Tur, J., Campion, D., Martinez, M., Brice, A., Tardieu, S., Hannequin, D., Agid, Y., Delacourte, A., Clerget-Darpoux, F., Chartier-Harlin, M.-C. and the French Alzheimer's disease collaborative group (1995) Evidence for apolipoprotein E [epsis]4 association in early-onset Alzheimer's patients with late-onset relatives. Am. J. Med. Genet., 60, 550-553. MEDLINE Abstract

4. Chartier-Harlin, M.-C., Parfitt, M., Legrain, S., Pérez-Tur, J., Brousseau, T., Evans, A., Berr, C., Vidal, O., Roques, P., Gourlet, V., Fruchart, J.C., Delacourte, A., Rossor, M. and Amouyel, P. (1994) Apolipoprotein E [epsis]4 allele as a major risk factor for sporadic early and late-onset forms of Alzheimer's disease: analysis of the 19q13.2 chromosomal region. Hum. Mol. Genet., 3, 569-574. MEDLINE Abstract

5. Diedrich, J.F., Minnigan, H., Carp, R.I., Whitaker, J.N., Race, R., Frey, W.,II and Haase, A.T. (1991) Neuropathological changes in Scrapie and Alzheimer's disease are associated with increased expression of Apolipoprotein E and Cathepsin D in astrocytes. J. Virol., 65, 4759-4768. MEDLINE Abstract

6. Poirier, J., Hess, M., May, P.C. and Finch, C.E. (1991) Astrocytic apolipoprotein E mRNA and GFAP mRNA in hippocampus after entorhinal cortex lesioning. Mol. Brain Res., 11, 97-106. MEDLINE Abstract

7. Malhey, R.W. (1988) Apolipoprotrein E: cholesterol transport protein with expanding role in cell biology. Science, 240, 622-630.

8. Leblanc, A.C. and Poduslo, J.F. (1990) Regulation of Apolipoprotein E gene expression after injury of the rat sciatic nerve. J. Neurosci. Res., 25, 162-171. MEDLINE Abstract

9. Guillaume, D., Dea, D., Davignon, J. and Poirier, J. (1995) Low-density lipoprotein pathways in the central nervous system and Apolipoprotein E isoform-specific differences. In Iqbal, Mortimer, Winblad and Wisniewski (eds) Research Advances in Alzheimer's Disease and Related Disorders. John Wiley and Son, pp. 386-395.

10. Bertrand, P., Poirier, J., Oda, T., Finch, C.E. and Pasinetti, G.M. (1995) Association of apolipoprotein E genotype with brain levels of apolipoprotein E apolipoprotein J (clusterin) in Alzheimer disease. Mol. Brain Res., 33, 174-178. MEDLINE Abstract

11. Lambert, J.-C., Pérez-Tur, J., Amouyel, P., Delacourte, A. and Chartier-Harlin, M.-C. (1997) Overcoming and normalisation of the signal saturation due to silver staining: a way to quantify allele specific RT-PCR products. Nucleic Acids Res., submitted.

12. Strittmatter, W.J, Weisgraber, K.H., Huang, D.Y., Dong, L.-M., Salvesen, G.S., Pericak-Vance, M., Schmechel, D., Saunders, A.M, Goldgaber, D. and Roses, A.D. (1993) Binding of human apolipoprotein E to synthetic amyloid [beta] peptide: isoform-specific effects and implications for late-onset Alzheimer disease. Proc. Natl. Acad. Sci. USA, 90, 8098-8102. MEDLINE Abstract

13. Evans, K., Berger, E.P., Cho, C.G., Weisgraber, K.H. and Lansburry, P.T. (1995) Apolipoprotein E is a kinetic but not a thermodynamic inhibitor of amyloid formation: implication for the pathogenesis and treatment of Alzheimer's disease. Proc. Natl. Acad. Sci. USA, 92, 763-767. MEDLINE Abstract

14. Miyata, M. and Smith, J.D. (1996) Apolipoprotein E allele-specific antioxidant activity and effects on cytotoxicity by oxidative insults and [beta]-amyloid peptides. Nature Genet., 14, 55-60. MEDLINE Abstract

15. Strittmatter, W.J., Weisgraber, K.H., Goedert, M., Saunders, A.M., Huang, D., Corder, E.H., Dong, L.-M., Jakes, R., Alberts, M.J., Gilbert, J.R., Han, S.H., Hulette, C., Einstein, G., Schmechel, D.E., Pericak-Vance, M.A. and Roses, A.D. (1994) Hypothesis: microtubule instability and paired helical filament formation in the Alzheimer disease are related to Apolipoprotein E genotype. Exp. Neurol., 125, 163-171. MEDLINE Abstract

16. Harr, S.D., Vint, L., Hollister, R., Hyman, B.T. and Mendez, A.J. (1996) Brain expression of Apolipoprotein E, J and A-I in Alzheimer's disease. J. Neurochem., 66, 2429-2435. MEDLINE Abstract

17. Lehtimäki, T., Pirttilä, T., Mehta, P.D., Wiesniewski, H.M., Frey, H. and Nikkari, T. (1995) Apolipoprotein E (apoE) polymorphism and its influence on ApoE concentrations in the cerebrospinal fluid in Finnish patients with Alzheimer's disease. Hum. Genet., 95, 39-42. MEDLINE Abstract

18. Lefranc, D., Vermersch, P., Dallongeville, J., Daems-Monpeurt, C., Petit, H. and Delacourte, A. (1996) Relevance of the quantification of apolipoprotein E in the cerebrospinal fluid in Alzheimer's disease. Neurosci. Lett., 212, 91-94. MEDLINE Abstract

19. Taddei, K., Clarnette, R., Gandy, S.E. and Martins, R.N. (1997) Increased plasma apolipoprotein E (apoE) levels in Alzheimer's disease. Neurosci. Lett., 223, 29-32. MEDLINE Abstract

20. Nukina, N., Uchida, K., Sakamoto, T., Ide, K. and Kanazawa, I. (1995) Monoclonal antibody against the polymorphic site distinguishes apolipoprotein [Egr]4 from other isoforms. Biochem. Biophys. Res. Com., 216, 467-472. MEDLINE Abstract

21. Ishimaru, H., Ishikawa, K., Haga, S., Shoji, M., Ohe, Y., Haga, C., Sasaki, A., Takashashi, A. and Maruyama, Y. (1996) Accumulation of apolipoprotein E and b-amyloid-like protein in a trace of the hippocampal CA1 pyramidal cell layer after ischaemic delayed neuronal death, Neuroreport, 7, 3063-3067. MEDLINE Abstract

22. Templeton, A.R. (1995) A cladistic analysis of phenotypic associations with haplotypes inferred from restriction endonuclease mapping or DNA sequencing. V. Analysis of case/control sampling designs: Alzheimer's disease and the Apolipoprotein E locus. Genetics, 140, 403-409. MEDLINE Abstract

23. Hixon, J.E. and Vernier, D.T. (1991) Restriction isotyping of human apolipoprotein E by gene amplification and cleavage with HhaI. J. Lipid Res., 31, 545-548.

24. Gilmour, R.S. and Dixon, G.H. (1972) Biosynthesis of protamine in trout testis. J. Biol. Chem., 247, 4621-4627. MEDLINE Abstract

*To whom correspondence should be addressed at: INSERM CJF95-05, Institut Pasteur de Lille, 1 rue de Calmette, 59019 Lille Cedex, France. Tel: +33 3 20 87 72 28; Fax: +33 3 20 87 78 94; Email: marie-christine.chartier-harlin@pasteur-lille.fr

This page is maintained by OUP admin. Last updated Sat Oct 18 13:41:19 BST 1997. Part of the OUP Journals World Wide Web service.
Copyright Oxford University Press, 1997


Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?


This article has been cited by other articles:


Home page
 J. Neurol. Neurosurg. PsychiatryHome page
J-C Lambert, D Mann, F Richard, J Tian, J Shi, U Thaker, S Merrot, J Harris, B Frigard, T Iwatsubo, et al.
Is there a relation between APOE expression and brain amyloid load in Alzheimer's disease?
J. Neurol. Neurosurg. Psychiatry, July 1, 2005; 76(7): 928 - 933.
[Abstract] [Full Text] [PDF]

Home page
 Hum Mol GenetHome page
N. J. Bray, L. Jehu, V. Moskvina, J. D. Buxbaum, S. Dracheva, V. Haroutunian, J. Williams, P. R. Buckland, M. J. Owen, and M. C. O'Donovan
Allelic expression of APOE in human brain: effects of epsilon status and promoter haplotypes
Hum. Mol. Genet., November 15, 2004; 13(22): 2885 - 2892.
[Abstract] [Full Text] [PDF]

Home page
 Hum Mol GenetHome page
A. Singleton, A. Myers, and J. Hardy
The law of mass action applied to neurodegenerative disease: a hypothesis concerning the etiology and pathogenesis of complex diseases
Hum. Mol. Genet., April 1, 2004; 13(90001): R123 - 126.
[Abstract] [Full Text] [PDF]

Home page
 J. Med. Genet.Home page
J-C Lambert, N Coyle, and C Lendon
The allelic modulation of apolipoprotein E expression by oestrogen: potential relevance for Alzheimer's disease
J. Med. Genet., February 1, 2004; 41(2): 104 - 112.
[Abstract] [Full Text] [PDF]

Home page
 J. Lipid Res.Home page
J. A. Moreno, J. Lopez-Miranda, C. Marin, P. Gomez, P. Perez-Martinez, F. Fuentes, R. A. Fernandez de la Puebla, J. A. Paniagua, J. M. Ordovas, and F. Perez-Jimenez
The influence of the apolipoprotein E gene promoter (-219G/ T) polymorphism on postprandial lipoprotein metabolism in young normolipemic males
J. Lipid Res., November 1, 2003; 44(11): 2059 - 2064.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Chem.Home page
E. M. Weidenhammer, B. F. Kahl, L. Wang, L. Wang, M. Duhon, J. A. Jackson, M. Slater, and X. Xu
Multiplexed, Targeted Gene Expression Profiling and Genetic Analysis on Electronic Microarrays
Clin. Chem., November 1, 2002; 48(11): 1873 - 1882.
[Abstract] [Full Text] [PDF]

Home page
 Hum Mol GenetHome page
J. Theuns and C. Van Broeckhoven
Transcriptional regulation of Alzheimer's disease genes: implications for susceptibility
Hum. Mol. Genet., October 1, 2000; 9(16): 2383 - 2394.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Pathol.Home page
I. Tesseur, J. Van Dorpe, K. Spittaels, C. Van den Haute, D. Moechars, and F. Van Leuven
Expression of Human Apolipoprotein E4 in Neurons Causes Hyperphosphorylation of Protein Tau in the Brains of Transgenic Mice
Am. J. Pathol., March 1, 2000; 156(3): 951 - 964.
[Abstract] [Full Text] [PDF]

Home page
 Hum Mol GenetHome page
J.-C. Lambert, T. Brousseau, V. Defosse, A. Evans, D. Arveiler, J.-B. Ruidavets, B. Haas, J.-P. Cambou, G. Luc, P. Ducimetiere, et al.
Independent association of an APOE gene promoter polymorphism with increased risk of myocardial infarction and decreased APOE plasma concentrations--the ECTIM Study
Hum. Mol. Genet., January 1, 2000; 9(1): 57 - 61.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Search for citing articles in:
ISI Web of Science (52)
Right arrowRequest Permissions
Google Scholar
Right arrow Articles by Lambert, J. C.
Right arrow Articles by Chartier-Harlin, M. C.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Lambert, J. C.
Right arrow Articles by Chartier-Harlin, M. C.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?