Skip to main content

Advertisement

SpringerLink
Log in

The alternative splicing of the apolipoprotein E gene is unperturbed in the brains of Alzheimer’s disease patients

  • Published:
Molecular Biology Reports Aims and scope Submit manuscript

Abstract

The prevalence of Alzheimer’s disease (AD) is increasing rapidly worldwide due to an ageing population and a lack of disease modifying therapeutics. In monogenic forms of AD mutations lead to the accumulation of neurotoxic peptides called beta-amyloid. Beta-amyloid accumulation is also postulated to precipitate sporadic AD although the pathogenesis of this common form remains largely unknown. The two leading risk factors for sporadic AD are ageing and the possession of the APOE epsilon 4 allele. Changes in APOE expression that are independent of the epsilon genotype have also been described in the AD brain including a recent RNA-Seq analysis that showed upregulation of a rare alternative splice isoform (APOE-005). To replicate these RNA-Seq findings we used quantitative reverse transcriptase polymerase chain reaction (RT-qPCR) to compare APOE-005 and total APOE expression in the superior temporal gyrus of 14 AD cases and 16 neurologically normal controls. In AD, this area shows prominent beta-amyloid deposition but few neurofibrillary tangles and only moderate neuronal loss. As poorer RNA quality among the AD cases was a likely confounder in this study, the analysis was repeated in a RIN-matched sub-cohort of 17 individuals. Contrary to the original RNA-Seq study, we found no difference in total APOE, APOE-005 or the common isoform, APOE-001, between AD cases and controls. Our findings are consistent with ApoE acting largely at the protein level to increase the risk for sporadic AD.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

Abbreviations

Aβ:

Amyloid-beta

ACTB:

Beta-actin

AD:

Alzheimer’s disease

ANOVA:

Analysis of variance

APOE:

Apolipoprotein E

APP:

Amyloid precursor protein

AT8:

A phospho-tau antibody

BACE1:

Beta-site APP-cleaving enzyme 1

BLAST:

Basic Local Alignment Search Tool

cDNA:

Copy DNA

Cq :

Quantification cycle

CLU:

Clusterin

DAB:

3,3′-Diaminobenzidine

DNA:

Deoxyribonucleic acid

FFPE:

Formalin-fixed paraffin-embedded

GAPDH:

Glyceraldehyde 3-phosphate dehydrogenase

GFAP:

Glial fibrillary acidic protein

GOI:

Gene of interest

HMBS:

Hydroxymethylbilane synthase

HPRT1:

Hypoxanthine phosphoribosyltransferase 1

mRNA:

Messenger RNA

HRP:

Horseradish peroxidase

MAPT:

Microtubule associated protein tau

NCBI:

National Center for Biotechnology Information

NFT:

Neurofibrillary tangle

NSWBB:

New South Wales Brain Banks

PMI:

Post mortem interval

PSEN1:

Presenilin-1

RG:

Reference gene

RNA:

Ribonucleic acid

RNA-Seq:

Next generation sequencing of the transcriptome

RT-qPCR:

Quantitative reverse transcriptase polymerase chain reaction

SDHA:

Succinate dehydrogenase complex, subunit A

STG:

Superior temporal gyrus

SNP:

Single nucleotide polymorphism

TSS:

Transcriptional start site

UBC:

Ubiquitin C

References

  1. Halliday GM, Double KL, Macdonald V, Kril JJ (2003) Identifying severely atrophic cortical subregions in Alzheimer’s disease. Neurobiol Aging 24(6):797–806

    Article  CAS  PubMed  Google Scholar 

  2. Gomez-Isla T, Price JL, McKeel DW Jr, Morris JC, Growdon JH, Hyman BT (1996) Profound loss of layer II entorhinal cortex neurons occurs in very mild Alzheimer’s disease. J Neurosci 16(14):4491–4500

    CAS  PubMed  Google Scholar 

  3. Hardy J, Selkoe DJ (2002) The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science 297(5580):353–356

    Article  CAS  PubMed  Google Scholar 

  4. McKhann GM, Knopman DS, Chertkow H, Hyman BT, Jack CR Jr, Kawas CH, Klunk WE, Koroshetz WJ, Manly JJ, Mayeux R, Mohs RC, Morris JC, Rossor MN, Scheltens P, Carrillo MC, Thies B, Weintraub S, Phelps CH (2011) The diagnosis of dementia due to Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement 7(3):263–269

    Article  PubMed Central  PubMed  Google Scholar 

  5. Lambert JC, Amouyel P (2011) Genetics of Alzheimer’s disease: new evidences for an old hypothesis? Curr Opin Genet Dev 21(3):295–301

    Article  CAS  PubMed  Google Scholar 

  6. Sutherland GT, Siebert GA, Kril JJ, Mellick GD (2011) Knowing me, knowing you: can a knowledge of risk factors for Alzheimer’s disease prove useful in understanding the pathogenesis of Parkinson’s disease? J Alzheimers Dis 25(3):395–415

    PubMed  Google Scholar 

  7. Ashford JW (2004) APOE genotype effects on Alzheimer’s disease onset and epidemiology. J Mol Neurosci 23(3):157–165

    Article  CAS  PubMed  Google Scholar 

  8. Chapman J, Korczyn AD, Karussis DM, Michaelson DM (2001) The effects of APOE genotype on age at onset and progression of neurodegenerative diseases. Neurology 57(8):1482–1485

    Article  CAS  PubMed  Google Scholar 

  9. Drzezga A, Grimmer T, Henriksen G, Muhlau M, Perneczky R, Miederer I, Praus C, Sorg C, Wohlschlager A, Riemenschneider M, Wester HJ, Foerstl H, Schwaiger M, Kurz A (2009) Effect of APOE genotype on amyloid plaque load and gray matter volume in Alzheimer disease. Neurology 72(17):1487–1494

    Article  CAS  PubMed  Google Scholar 

  10. Ramanan VK, Risacher SL, Nho K, Kim S, Swaminathan S, Shen L, Foroud TM, Hakonarson H, Huentelman MJ, Aisen PS, Petersen RC, Green RC, Jack CR, Koeppe RA, Jagust WJ, Weiner MW, Saykin AJ (2014) APOE and BCHE as modulators of cerebral amyloid deposition: a florbetapir PET genome-wide association study. Mol Psychiatry 19(3):351–357

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  11. Schmechel DE, Saunders AM, Strittmatter WJ, Crain BJ, Hulette CM, Joo SH, Pericak-Vance MA, Goldgaber D, Roses AD (1993) Increased amyloid beta-peptide deposition in cerebral cortex as a consequence of apolipoprotein E genotype in late-onset Alzheimer disease. Proc Natl Acad Sci USA 90(20):9649–9653

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  12. Christensen DZ, Schneider-Axmann T, Lucassen PJ, Bayer TA, Wirths O (2010) Accumulation of intraneuronal Abeta correlates with ApoE4 genotype. Acta Neuropathol 119(5):555–566

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  13. Sabbagh MN, Malek-Ahmadi M, Dugger BN, Lee K, Sue LI, Serrano G, Walker DG, Davis K, Jacobson SA, Beach TG (2013) The influence of Apolipoprotein E genotype on regional pathology in Alzheimer’s disease. BMC Neurol 13:44

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  14. Liu CC, Kanekiyo T, Xu H, Bu G (2013) Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy. Nat Rev Neurol 9(2):106–118

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  15. Strittmatter WJ, Weisgraber KH, Huang DY, Dong LM, Salvesen GS, Pericak-Vance M, Schmechel D, Saunders AM, Goldgaber D, Roses AD (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(17):8098–8102

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  16. Huang Y, Liu XQ, Wyss-Coray T, Brecht WJ, Sanan DA, Mahley RW (2001) Apolipoprotein E fragments present in Alzheimer’s disease brains induce neurofibrillary tangle-like intracellular inclusions in neurons. Proc Natl Acad Sci USA 98(15):8838–8843

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  17. Bekris LM, Galloway NM, Montine TJ, Schellenberg GD, Yu CE (2010) APOE mRNA and protein expression in postmortem brain are modulated by an extended haplotype structure. Am J Med Genet B 153B(2):409–417

    CAS  Google Scholar 

  18. Bullido MJ, Artiga MJ, Recuero M, Sastre I, Garcia MA, Aldudo J, Lendon C, Han SW, Morris JC, Frank A, Vazquez J, Goate A, Valdivieso F (1998) A polymorphism in the regulatory region of APOE associated with risk for Alzheimer’s dementia. Nat Genet 18(1):69–71

    Article  CAS  PubMed  Google Scholar 

  19. Lambert JC, Pasquier F, Cottel D, Frigard B, Amouyel P, Chartier-Harlin MC (1998) A new polymorphism in the APOE promoter associated with risk of developing Alzheimer’s disease. Hum Mol Genet 7(3):533–540

    Article  CAS  PubMed  Google Scholar 

  20. Wang JC, Kwon JM, Shah P, Morris JC, Goate A (2000) Effect of APOE genotype and promoter polymorphism on risk of Alzheimer’s disease. Neurology 55(11):1644–1649

    Article  CAS  PubMed  Google Scholar 

  21. Marioni JC, Mason CE, Mane SM, Stephens M, Gilad Y (2008) RNA-seq: an assessment of technical reproducibility and comparison with gene expression arrays. Genome Res 18(9):1509–1517

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  22. Sutherland GT, Janitz M, Kril JJ (2011) Understanding the pathogenesis of Alzheimer’s disease: will RNA-Seq realize the promise of transcriptomics? J Neurochem 116(6):937–946

    Article  CAS  PubMed  Google Scholar 

  23. Twine NA, Janitz K, Wilkins MR, Janitz M (2011) Whole transcriptome sequencing reveals gene expression and splicing differences in brain regions affected by Alzheimer’s disease. PLoS ONE 6(1):e16266

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  24. Flicek P, Amode MR, Barrell D, Beal K, Brent S, Carvalho-Silva D, Clapham P, Coates G, Fairley S, Fitzgerald S, Gil L, Gordon L, Hendrix M, Hourlier T, Johnson N, Kahari AK, Keefe D, Keenan S, Kinsella R, Komorowska M, Koscielny G, Kulesha E, Larsson P, Longden I, McLaren W, Muffato M, Overduin B, Pignatelli M, Pritchard B, Riat HS, Ritchie GR, Ruffier M, Schuster M, Sobral D, Tang YA, Taylor K, Trevanion S, Vandrovcova J, White S, Wilson M, Wilder SP, Aken BL, Birney E, Cunningham F, Dunham I, Durbin R, Fernandez-Suarez XM, Harrow J, Herrero J, Hubbard TJ, Parker A, Proctor G, Spudich G, Vogel J, Yates A, Zadissa A, Searle SM (2012) Ensembl 2012. Nucleic Acids Res 40(Database issue):D84–D90

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  25. NIA-Reagan Institute Working Group (1997) Consensus recommendations for the postmortem diagnosis of Alzheimer’s disease. The National Institute on Aging, and Reagan Institute Working Group on Diagnostic Criteria for the Neuropathological Assessment of Alzheimer’s Disease. Neurobiol Aging 18(4 Suppl):S1–S2

    Google Scholar 

  26. Uchihara T, Nakamura A, Yamazaki M, Mori O (2001) Evolution from pretangle neurons to neurofibrillary tangles monitored by thiazine red combined with Gallyas method and double immunofluorescence. Acta Neuropathol 101(6):535–539

    CAS  PubMed  Google Scholar 

  27. Garcia-Sierra F, Hauw JJ, Duyckaerts C, Wischik CM, Luna-Munoz J, Mena R (2000) The extent of neurofibrillary pathology in perforant pathway neurons is the key determinant of dementia in the very old. Acta Neuropathol 100(1):29–35

    Article  CAS  PubMed  Google Scholar 

  28. Bustin SA, Benes V, Garson JA, Hellemans J, Huggett J, Kubista M, Mueller R, Nolan T, Pfaffl MW, Shipley GL, Vandesompele J, Wittwer CT (2009) The MIQE guidelines: minimum information for publication of quantitative real-time PCR experiments. Clin Chem 55(4):611–622

    Article  CAS  PubMed  Google Scholar 

  29. Vandesompele J, De Preter K, Pattyn F, Poppe B, Van Roy N, De Paepe A, Speleman F (2002) Accurate normalization of real-time quantitative RT-PCR data by geometric averaging of multiple internal control genes. Genome Biol 3(7). doi:10.1186/gb-2002-3-7-research0034

  30. Pattyn F, Speleman F, De Paepe A, Vandesompele J (2003) RTPrimerDB: the real-time PCR primer and probe database. Nucleic Acids Res 31(1):122–123

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  31. Uchihara T, Nakamura A, Yamazaki M, Mori O, Ikeda K, Tsuchiya K (2001) Different conformation of neuronal tau deposits distinguished by double immunofluorescence with AT8 and thiazin red combined with Gallyas method. Acta Neuropathol 102(5):462–466

    CAS  PubMed  Google Scholar 

  32. Barrachina M, Castano E, Ferrer I (2006) TaqMan PCR assay in the control of RNA normalization in human post-mortem brain tissue. Neurochem Int 49(3):276–284

    Article  CAS  PubMed  Google Scholar 

  33. Li JZ, Vawter MP, Walsh DM, Tomita H, Evans SJ, Choudary PV, Lopez JF, Avelar A, Shokoohi V, Chung T, Mesarwi O, Jones EG, Watson SJ, Akil H, Bunney WE Jr, Myers RM (2004) Systematic changes in gene expression in postmortem human brains associated with tissue pH and terminal medical conditions. Hum Mol Genet 13(6):609–616

    Article  CAS  PubMed  Google Scholar 

  34. Bai B, Hales CM, Chen PC, Gozal Y, Dammer EB, Fritz JJ, Wang X, Xia Q, Duong DM, Street C, Cantero G, Cheng D, Jones DR, Wu Z, Li Y, Diner I, Heilman CJ, Rees HD, Wu H, Lin L, Szulwach KE, Gearing M, Mufson EJ, Bennett DA, Montine TJ, Seyfried NT, Wingo TS, Sun YE, Jin P, Hanfelt J, Willcock DM, Levey A, Lah JJ (2013) Peng J (2013) U1 small nuclear ribonucleoprotein complex and RNA splicing alterations in Alzheimer’s disease. Proc Natl Acad Sci USA 110(41):16562–16567

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  35. Atz M, Walsh D, Cartagena P, Li J, Evans S, Choudary P, Overman K, Stein R, Tomita H, Potkin S, Myers R, Watson SJ, Jones EG, Akil H, Bunney WE Jr, Vawter MP (2007) Methodological considerations for gene expression profiling of human brain. J Neurosci Methods 163(2):295–309

    Article  CAS  PubMed  Google Scholar 

  36. Durrenberger PF, Fernando S, Kashefi SN, Ferrer I, Hauw JJ, Seilhean D, Smith C, Walker R, Al-Sarraj S, Troakes C, Palkovits M, Kasztner M, Huitinga I, Arzberger T, Dexter DT, Kretzschmar H, Reynolds R (2010) Effects of antemortem and postmortem variables on human brain mRNA quality: a BrainNet Europe study. J Neuropathol Exp Neurol 69(1):70–81

    Article  PubMed  Google Scholar 

  37. Weis S, Llenos IC, Dulay JR, Elashoff M, Martinez-Murillo F, Miller CL (2007) Quality control for microarray analysis of human brain samples: the impact of postmortem factors, RNA characteristics, and histopathology. J Neurosci Methods 165(2):198–209

    Article  CAS  PubMed  Google Scholar 

  38. Barton AJ, Pearson RC, Najlerahim A, Harrison PJ (1993) Pre- and postmortem influences on brain RNA. J Neurochem 61(1):1–11

    Article  CAS  PubMed  Google Scholar 

  39. Yates CM, Butterworth J, Tennant MC, Gordon A (1990) Enzyme activities in relation to pH and lactate in postmortem brain in Alzheimer-type and other dementias. J Neurochem 55(5):1624–1630

    Article  CAS  PubMed  Google Scholar 

  40. Monoranu CM, Apfelbacher M, Grunblatt E, Puppe B, Alafuzoff I, Ferrer I, Al-Saraj S, Keyvani K, Schmitt A, Falkai P, Schittenhelm J, Halliday G, Kril J, Harper C, McLean C, Riederer P, Roggendorf W (2009) pH measurement as quality control on human post mortem brain tissue: a study of the BrainNet Europe consortium. Neuropathol Appl Neurobiol 35(3):329–337

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  41. Sutherland GT, Sheedy D (2014) Kril JJ (2013) Using autopsy brain tissue to study alcohol-related brain damage in the genomic age Alcoholism. Alcohol Clin Exp Res 38(1):1–8

    Article  PubMed Central  PubMed  Google Scholar 

  42. Tomita H, Vawter MP, Walsh DM, Evans SJ, Choudary PV, Li J, Overman KM, Atz ME, Myers RM, Jones EG, Watson SJ, Akil H, Bunney WE Jr (2004) Effect of agonal and postmortem factors on gene expression profile: quality control in microarray analyses of postmortem human brain. Biol Psychiatry 55(4):346–352

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  43. Broniscer A, Baker JN, Baker SJ, Chi SN, Geyer JR, Morris EB, Gajjar A (2010) Prospective collection of tissue samples at autopsy in children with diffuse intrinsic pontine glioma. Cancer 116(19):4632–4637

    Article  PubMed Central  PubMed  Google Scholar 

  44. Trabzuni D, Ryten M, Walker R, Smith C, Imran S, Ramasamy A, Weale ME, Hardy J (2011) Quality control parameters on a large dataset of regionally dissected human control brains for whole genome expression studies. J Neurochem 119(2):275–282

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  45. Roth RB, Hevezi P, Lee J, Willhite D, Lechner SM, Foster AC, Zlotnik A (2006) Gene expression analyses reveal molecular relationships among 20 regions of the human CNS. Neurogenetics 7(2):67–80

    Article  CAS  PubMed  Google Scholar 

  46. Vermeulen J, De Preter K, Lefever S, Nuytens J, De Vloed F, Derveaux S, Hellemans J, Speleman F, Vandesompele J (2011) Measurable impact of RNA quality on gene expression results from quantitative PCR. Nucleic Acids Res 39(9):e63

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  47. Mexal S, Berger R, Adams CE, Ross RG, Freedman R, Leonard S (2006) Brain pH has a significant impact on human postmortem hippocampal gene expression profiles. Brain Res 1106(1):1–11

    Article  CAS  PubMed  Google Scholar 

  48. Vawter MP, Tomita H, Meng F, Bolstad B, Li J, Evans S, Choudary P, Atz M, Shao L, Neal C, Walsh DM, Burmeister M, Speed T, Myers R, Jones EG, Watson SJ, Akil H, Bunney WE (2006) Mitochondrial-related gene expression changes are sensitive to agonal-pH state: implications for brain disorders. Mol Psychiatry 11(7):615, 663-679

    Google Scholar 

  49. Sutherland GT, Sheedy D, Sheahan PJ, Kaplan W, Kril JJ (2014) Comorbidities, confounders, and the white matter transcriptome in chronic alcoholism. Alcohol Clin Exp Res 38(4):994–1001

  50. Coulson DT, Brockbank S, Quinn JG, Murphy S, Ravid R, Irvine GB, Johnston JA (2008) Identification of valid reference genes for the normalization of RT qPCR gene expression data in human brain tissue. BMC Mol Biol 9:46

    Article  PubMed Central  PubMed  Google Scholar 

  51. Wang Q, Ishikawa T, Michiue T, Zhu BL, Guan DW, Maeda H (2012) Stability of endogenous reference genes in postmortem human brains for normalization of quantitative real-time PCR data: comprehensive evaluation using geNorm, NormFinder, and BestKeeper. Int J Legal Med 126(6):943–952

    Article  PubMed  Google Scholar 

  52. Coulson DT, Beyer N, Quinn JG, Brockbank S, Hellemans J, Irvine GB, Ravid R, Johnston JA (2010) BACE1 mRNA expression in Alzheimer’s disease postmortem brain tissue. J Alzheimers Dis 22(4):1111–1122

    CAS  PubMed  Google Scholar 

  53. Rhinn H, Fujita R, Qiang L, Cheng R, Lee JH, Abeliovich A (2013) Integrative genomics identifies APOE epsilon4 effectors in Alzheimer’s disease. Nature 500(7460):45–50

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The authors would like to thank the donors and their families for their kind gift that has allowed this research to be undertaken. A special thanks to A/Prof David Sullivan and Terrance Foo from Department of Clinical Biochemistry, Royal Prince Alfred Hospital, Sydney, for the APOE genotyping. We also thank the New South Wales Brain Bank Network for providing tissue samples and assistance with clinical and pathological data. The Network is made up of the Sydney Brain Bank (SBB) and NSW Tissue Resource Centre (NSW TRC). The SBB is supported by Neuroscience Research Australia, the University of New South Wales, the National Health and Medical Research Council (NHMRC) and the Australian Brain Bank Network. NSW TRC is supported by the University of Sydney, NHMRC (#605210), the Schizophrenia Research Institute and the National Institutes of Alcoholism and Alcohol Abuse (NIAAA; R24 AA012725).

Author information

Authors and Affiliations

  1. School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW, 2052, Australia

    James D. Mills & Michael Janitz

  2. Discipline of Pathology, Sydney Medical School, University of Sydney, Blackburn Building D06, NSW, 2006, Australia

    Pamela J. Sheahan, Jillian J. Kril & Greg T. Sutherland

  3. Discipline of Medicine, Sydney Medical School, University of Sydney, Sydney, NSW, 2006, Australia

    Jillian J. Kril

  4. Bosch Research Institute, University of Sydney, Sydney, NSW, 2006, Australia

    Donna Lai

Authors
  1. James D. Mills
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Pamela J. Sheahan
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Donna Lai
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jillian J. Kril
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Michael Janitz
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Greg T. Sutherland
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Greg T. Sutherland.

Additional information

James D. Mills and Pamela J. Sheahan have contributed equally to this work.

Electronic supplementary material

Below is the link to the electronic supplementary material.

11033_2014_3516_MOESM1_ESM.xls

Supplementary Table S1. This table contains all demographic, clinical, pathological, RNA quality and RT-qRCR raw and normalized data (GFAP as the reference gene) for the total cohort (n = 29)

11033_2014_3516_MOESM2_ESM.xls

Supplementary Table S2. This table contains all demographic, clinical, pathological, RNA quality and RT-qRCR raw and normalized data (GFAP as the reference gene) in a RIN-matched sub-cohort of 17 AD cases and controls

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Mills, J.D., Sheahan, P.J., Lai, D. et al. The alternative splicing of the apolipoprotein E gene is unperturbed in the brains of Alzheimer’s disease patients. Mol Biol Rep 41, 6365–6376 (2014). https://doi.org/10.1007/s11033-014-3516-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11033-014-3516-8

Keywords

Search

Navigation