Abstract
Alzheimer's disease (AD) is a neurodegenerative condition characterized histopathologically by neuritic plaques and neurofibrillary tangles. The objective of this transcriptional profiling study was to identify both neurosusceptibility and intrinsic neuroprotective factors at the molecular level, not confounded by the downstream consequences of pathology. We thus studied post-mortem cortical tissue in 28 cases that were non-APOE4 carriers (called the APOE3 group) and 13 cases that were APOE4 carriers. As APOE genotype is the major genetic risk factor for late-onset AD, the former group was at low risk for development of the disease and the latter group was at high risk for the disease. Mean age at death was 42 years and none of the brains had histopathology diagnostic of AD at the time of death. We first derived interregional difference scores in expression between cortical tissue from a region relatively invulnerable to AD (primary somatosensory cortex, BA 1/2/3) and an area known to be susceptible to AD pathology (middle temporal gyrus, BA 21). We then contrasted the magnitude of these interregional differences in between-group comparisons of the APOE3 (low risk) and APOE4 (high risk) genotype groups. We identified 70 transcripts that differed significantly between the groups. These included EGFR, CNTFR, CASP6, GRIA2, CTNNB1, FKBPL, LGALS1 and PSMC5. Using real-time quantitative PCR, we validated these findings. In addition, we found regional differences in the expression of APOE itself. We also identified multiple Kyoto pathways that were disrupted in the APOE4 group, including those involved in mitochondrial function, calcium regulation and cell-cycle reentry. To determine the functional significance of our transcriptional findings, we used bioinformatics pathway analyses to demonstrate that the molecules listed above comprised a network of connections with each other, APOE, and APP and MAPT. Overall, our results indicated that the abnormalities that we observed in single transcripts and in signaling pathways were not the consequences of diagnostic plaque and tangle pathology, but preceded it and thus may be a causative link in the long molecular prodrome that results in clinical AD.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Braak H, Del Tredici K, Schultz C, Braak E . Vulnerability of select neuronal types to Alzheimer's disease. Ann NY Acad Sci 2000; 924: 53–61.
Haroutunian V, Katsel P, Schmeidler J . Transcriptional vulnerability of brain regions in Alzheimer's disease and dementia. Neurobiol Aging 2007; 30: 561–573.
Arnold SE, Hyman BT, Flory J, Damasio AR, Van Hoesen GW . The topographical and neuroanatomical distribution of neurofibrillary tangles and neuritic plaques in the cerebral cortex of patients with Alzheimer's disease. Cerebral Cortex 1991; 1: 103–116.
Brun A, Gustafson L . Distribution of cerebral degeneration in Alzheimer's disease. A clinico-pathological study. Archiv fur Psychiatrie und Nervenkrankheiten 1976; 223: 15–33.
Coon KD, Myers AJ, Craig DW, Webster JA, Pearson JV, Lince DH et al. A high-density whole-genome association study reveals that APOE is the major susceptibility gene for sporadic late-onset Alzheimer's disease.[see comment]. J Clin Psychiatry 2007; 68: 613–618.
Reddy PH, McWeeney S . Mapping cellular transcriptosomes in autopsied Alzheimer's disease subjects and relevant animal models.[see comment]. Neurobiol Aging 2006; 27: 1060–1077.
Katsel PL, Davis KL, Haroutunian V . Large-scale microarray studies of gene expression in multiple regions of the brain in schizophrenia and Alzheimer's disease. Int Rev Neurobiol 2005; 63: 41–82.
Harrison PJ, Heath PR, Eastwood SL, Burnet PW, McDonald B, Pearson RC . The relative importance of premortem acidosis and postmortem interval for human brain gene expression studies: selective mRNA vulnerability and comparison with their encoded proteins. Neurosci Lett 1995; 200: 151–154.
Mirnics K, Levitt P, Lewis DA . DNA microarray analysis of postmortem brain tissue. Int Rev Neurobiol 2004; 60: 153–181.
Conejero-Goldberg C, Wang E, Yi C, Goldberg TE, Jones-Brando L, Marincola FM et al. Infectious pathogen detection arrays: viral detection in cell lines and postmortem brain tissue. Biotechniques 2005; 39: 741–751.
Khachaturian ZS . Diagnosis of Alzheimer's disease. Arch Neurol 1985; 42: 1097–1105.
Hixson JE, Vernier DT . Restriction isotyping of human apolipoprotein E by gene amplification and cleavage with HhaI. J Lipid Res 1990; 31: 545–548.
Barnes M, Freudenberg J, Thompson S, Aronow B, Pavlidis P . Experimental comparison and cross-validation of the Affymetrix and Illumina gene expression analysis platforms. Nucleic Acids Res 2005; 33: 5914–5923.
McShane LM, Radmacher MD, Freidlin B, Yu R, Li MC, Simon R . Methods for assessing reproducibility of clustering patterns observed in analyses of microarray data. Bioinformatics 2002; 18: 1462–1469.
Calvano SE, Xiao W, Richards DR, Felciano RM, Baker HV, Cho RJ et al. A network-based analysis of systemic inflammation in humans. [published erratum appears in Nature 2005;438: 696] Nature 2005; 437: 1032–1037.
LeBlanc AC . The role of apoptotic pathways in Alzheimer's disease neurodegeneration and cell death. Curr Alzheimer Res 2005; 2: 389–402.
Nikolaev A, McLaughlin T, O’Leary DD, Tessier-Lavigne M . APP binds DR6 to trigger axon pruning and neuron death via distinct caspases.[see comment]. Nature 2009; 457: 981–989.
Klaiman G, Petzke TL, Hammond J, Leblanc AC . Targets of caspase-6 activity in human neurons and Alzheimer's disease. Mol Cell Proteomics 2008; 7: 1541–1555.
Yasuda RP, Ikonomovic MD, Sheffield R, Rubin RT, Wolfe BB, Armstrong DM . Reduction of AMPA-selective glutamate receptor subunits in the entorhinal cortex of patients with Alzheimer's disease pathology: a biochemical study. Brain Res 1995; 678: 161–167.
Carter TL, Rissman RA, Mishizen-Eberz AJ, Wolfe BB, Hamilton RL, Gandy S et al. Differential preservation of AMPA receptor subunits in the hippocampi of Alzheimer's disease patients according to Braak stage. Exp Neurol 2004; 187: 299–309.
Altar CA, Vawter MP, Ginsberg SD . Target identification for CNS diseases by transcriptional profiling. Neuropsychopharmacol Rev 2009; 34: 18–54.
Zhang YW, Wang R, Liu Q, Zhang H, Liao FF, Xu H . Presenilin/gamma-secretase-dependent processing of beta-amyloid precursor protein regulates EGF receptor expression. Proc Natl Acad Sci USA 2007; 104: 10613–10618.
Repetto E, Yoon IS, Zheng H, Kang DE . Presenilin 1 regulates epidermal growth factor receptor turnover and signaling in the endosomal-lysosomal pathway. J Biol Chem 2007; 282: 31504–31516.
Cha YK, Kim YH, Ahn YH, Koh JY . Epidermal growth factor induces oxidative neuronal injury in cortical culture. J Neurochem 2000; 75: 298–303.
Kang CB, Hong Y, Dhe-Paganon S, Yoon HS . FKBP family proteins: immunophilins with versatile biological functions. Neurosignals 2008; 16: 318–325.
Hoeffer CA, Tang W, Wong H, Santillan A, Patterson RJ, Martinez LA et al. Removal of FKBP12 enhances mTOR-Raptor interactions, LTP, memory, and perseverative/repetitive behavior. Neuron 2008; 60: 832–845.
Wang HQ, Nakaya Y, Du Z, Yamane T, Shirane M, Kudo T et al. Interaction of presenilins with FKBP38 promotes apoptosis by reducing mitochondrial Bcl-2. Hum Mol Genet 2005; 14: 1889–1902.
Gutman CR, Strittmatter WJ, Weisgraber KH, Matthew WD . Apolipoprotein E binds to and potentiates the biological activity of ciliary neurotrophic factor. J Neurosci 1997; 17: 6114–6121.
Qu HY, Zhang T, Li XL, Zhou JP, Zhao BQ, Li Q et al. Transducible P11-CNTF rescues the learning and memory impairments induced by amyloid-beta peptide in mice. Eur J Pharmacol 2008; 594: 93–100.
Laity JH, Lee BM, Wright PE . Zinc finger proteins: new insights into structural and functional diversity. Curr Opin Struct Biol 2001; 11: 39–46.
Maguschak KA, Ressler KJ . Beta-catenin is required for memory consolidation. Nature Neurosci 2008; 11: 1319–1326.
Sasaki T, Hirabayashi J, Manya H, Kasai K, Endo T . Galectin-1 induces astrocyte differentiation, which leads to production of brain-derived neurotrophic factor. Glycobiology 2004; 14: 357–363.
Cooper D, Norling LV, Perretti M . Novel insights into the inhibitory effects of Galectin-1 on neutrophil recruitment under flow. J Leukoc Biol 2008; 83: 1459–1466.
La M, Cao TV, Cerchiaro G, Chilton K, Hirabayashi J, Kasai K et al. A novel biological activity for galectin-1: inhibition of leukocyte-endothelial cell interactions in experimental inflammation. Am J Pathol 2003; 163: 1505–1515.
Matsuda A, Suzuki Y, Honda G, Muramatsu S, Matsuzaki O, Nagano Y et al. Large-scale identification and characterization of human genes that activate NF-kappaB and MAPK signaling pathways. Oncogene 2003; 22: 3307–3318.
Zhang JY, Liu SJ, Li HL, Wang JZ . Microtubule-associated protein tau is a substrate of ATP/Mg(2+)-dependent proteasome protease system. J Neural Transm 2005; 112: 547–555.
Lopez Salon M, Pasquini L, Besio Moreno M, Pasquini JM, Soto E . Relationship between beta-amyloid degradation and the 26S proteasome in neural cells. Exp Neurol 2003; 180: 131–143.
Cecarini V, Bonfili L, Amici M, Angeletti M, Keller JN, Eleuteri AM . Amyloid peptides in different assembly states and related effects on isolated and cellular proteasomes. Brain Res 2008; 1209: 8–18.
Hoglinger GU, Carrard G, Michel PP, Medja F, Lombes A, Ruberg M et al. Dysfunction of mitochondrial complex I and the proteasome: interactions between two biochemical deficits in a cellular model of Parkinson's disease. J Neurochem 2003; 86: 1297–1307.
Stutzmann GE . The pathogenesis of Alzheimer's disease is it a lifelong ‘calciumopathy’? Neuroscientist 2007; 13: 546–559.
LaFerla FM . Calcium dyshomeostasis and intracellular signalling in Alzheimer's disease. Nat Rev Neurosci 2002; 3: 862–872.
Dreses-Werringloer U, Lambert JC, Vingtdeux V, Zhao H, Vais H, Siebert A et al. A polymorphism in CALHM1 influences Ca2+ homeostasis, Abeta levels, and Alzheimer's disease risk. Cell 2008; 133: 1149–1161.
Mudher A, Lovestone S . Alzheimer's disease-do tauists and baptists finally shake hands? Trends Neurosci 2002; 25: 22–26.
De Strooper B, Annaert W . Where Notch and Wnt signaling meet. The presenilin hub. J Cell Biol 2001; 152: 785–794.
Andorfer C, Acker CM, Kress Y, Hof PR, Duff K, Davies P . Cell-cycle reentry and cell death in transgenic mice expressing nonmutant human tau isoforms. J Neurosci 2005; 25: 5446–5454.
Herrup K, Arendt T . Re-expression of cell cycle proteins induces neuronal cell death during Alzheimer's disease.[see comment]. J Alzheimers Dis 2002; 4: 243–247.
Herrup K, Neve R, Ackerman SL, Copani A . Divide and die: cell cycle events as triggers of nerve cell death. J Neurosci 2004; 24: 9232–9239.
Yang Y, Mufson EJ, Herrup K . Neuronal cell death is preceded by cell cycle events at all stages of Alzheimer's disease. J Neurosci 2003; 23: 2557–2563.
Mattson MP, Keller JN, Begley JG . Evidence for synaptic apoptosis. Exp Neurol 1998; 153: 35–48.
Albrecht S, Bourdeau M, Bennett D, Mufson EJ, Bhattacharjee M, LeBlanc AC . Activation of caspase-6 in aging and mild cognitive impairment. Am J Pathol 2007; 170: 1200–1209.
Zhong N, Scearce-Levie K, Ramaswamy G, Weisgraber KH . Apolipoprotein E4 domain interaction: synaptic and cognitive deficits in mice. Alzheimers Dement 2008; 4: 179–192.
Mahley RW, Huang Y . Apolipoprotein (apo) E4 and Alzheimer's disease: unique conformational and biophysical properties of apoE4 can modulate neuropathology. Acta Neurologica Scandinavica Supplementum 2006; 185: 8–14.
Reddy PH, Beal MF . Are mitochondria critical in the pathogenesis of Alzheimer's disease? Brain Res Rev 2005; 49: 618–632.
Lin MT, Beal MF . Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature 2006; 443: 787–795.
Starkov AA, Beal FM . Portal to Alzheimer's disease.[comment]. Nat Med 2008; 14: 1020–1021.
Smith MA, Drew KL, Nunomura A, Takeda A, Hirai K, Zhu X et al. Amyloid-beta, tau alterations and mitochondrial dysfunction in Alzheimer disease: the chickens or the eggs? Neurochem Int 2002; 40: 527–531.
Andersen JK . Oxidative stress in neurodegeneration: cause or consequence? Nat Med 2004; 10 (Suppl): S18–S25.
Liang WS, Reiman EM, Valla J, Dunckley T, Beach TG, Grover A et al. Alzheimer's disease is associated with reduced expression of energy metabolism genes in posterior cingulate neurons. Proc Natl Acad Sci USA 2008; 105: 4441–4446.
Rhein V, Song X, Wiesner A, Ittner LM, Baysang G, Meier F et al. Amyloid-beta and tau synergistically impair the oxidative phosphorylation system in triple transgenic Alzheimer's disease mice. Pro Natl Acad Sci USA 2009; 106: 20057–20062.
Hardy J, Selkoe DJ . The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics.[see comment]. [published erratum appears in Science 2002; 297: 2209] Science 2002; 297: 353–356.
Xu PT, Li YJ, Qin XJ, Scherzer CR, Xu H, Schmechel DE et al. Differences in apolipoprotein E3/3 and E4/4 allele-specific gene expression in hippocampus in Alzheimer disease. Neurobiol Dis 2006; 21: 256–275.
Liang WS, Dunckley T, Beach TG, Grover A, Mastroeni D, Ramsey K et al. Altered neuronal gene expression in brain regions differentially affected by Alzheimer's disease: a reference data set. Physiol Genom 2008; 33: 240–256.
Blalock EM, Geddes JW, Chen KC, Porter NM, Markesbery WR, Landfield PW . Incipient Alzheimer's disease: microarray correlation analyses reveal major transcriptional and tumor suppressor responses. Proc Natl Acad Sci USA 2004; 101: 2173–2178.
Ginsberg SD, Hemby SE, Lee VM, Eberwine JH, Trojanowski JQ . Expression profile of transcripts in Alzheimer's disease tangle-bearing CA1 neurons. Ann Neurol 2000; 48: 77–87.
Dunckley T, Beach TG, Ramsey KE, Grover A, Mastroeni D, Walker DG et al. Gene expression correlates of neurofibrillary tangles in Alzheimer's disease. Neurobiol Aging 2006; 27: 1359–1371.
Reiman EM, Chen K, Alexander GE, Caselli RJ, Bandy D, Osborne D et al. Functional brain abnormalities in young adults at genetic risk for late-onset Alzheimer's dementia. Proc Natl Acad Sci USA 2004; 101: 284–289.
Bookheimer SY, Strojwas MH, Cohen MS, Saunders AM, Pericak-Vance MA, Mazziotta JC et al. Patterns of brain activation in people at risk for Alzheimer's disease.[see comment]. N Engl J Med 2000; 343: 450–456.
Caselli RJ, Dueck AC, Osborne D, Sabbagh MN, Connor DJ, Ahern GL et al. Longitudinal modeling of age-related memory decline and the APOE epsilon4 effect. N Engl J Med 2009; 361: 255–263.
Palop JJ, Chin J, Mucke L . A network dysfunction perspective on neurodegenerative diseases. Nature 2006; 443: 768–773.
Acknowledgements
We thank Dr Richard Simon for providing expert statistical advice and Ms Amy Deep-Soboslay and Dr Llewellyn Bigelow for post-mortem patient screening and diagnosis. We thank Mr Brady Kirchberg for providing expertise in graphical display. We also thank Dr Franak Batliwalla and Ms Aarti Damle, members of the Feinstein Institute's microarray core facility, for their assistance.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
TG has consulted for Merck and GSK. He receives royalties for use of a cognitive test battery in clinical trials, the BACS. He has received an investigator initiated grant from Eisai/Pfizer. PD has received research support from and served as a consultant to Applied Neurosolutions. The remaining authors declare no conflict of interest.
Additional information
Supplementary Information accompanies the paper on the Molecular Psychiatry website
Supplementary information
Rights and permissions
About this article
Cite this article
Conejero-Goldberg, C., Hyde, T., Chen, S. et al. Molecular signatures in post-mortem brain tissue of younger individuals at high risk for Alzheimer's disease as based on APOE genotype. Mol Psychiatry 16, 836–847 (2011). https://doi.org/10.1038/mp.2010.57
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/mp.2010.57
Keywords
This article is cited by
-
Neuronal Stem Cells from Late-Onset Alzheimer Patients Show Altered Regulation of Sirtuin 1 Depending on Apolipoprotein E Indicating Disturbed Stem Cell Plasticity
Molecular Neurobiology (2024)
-
Artificial intelligence framework identifies candidate targets for drug repurposing in Alzheimer’s disease
Alzheimer's Research & Therapy (2022)
-
The APOE locus is linked to decline in general cognitive function: 20-years follow-up in the Doetinchem Cohort Study
Translational Psychiatry (2022)
-
Alzheimer’s Disease Genetics: Review of Novel Loci Associated with Disease
Current Genetic Medicine Reports (2020)
-
Analyzing the genes related to Alzheimer’s disease via a network and pathway-based approach
Alzheimer's Research & Therapy (2017)