GSE5281 Human Brain Best 102 Liang (Jul09) RMA

Summary

(Taken verbatim from the GEO record)

Information about the genes that are preferentially expressed during the course of Alzheimer’s disease (AD) could improve our understanding of the molecular mechanisms involved in the pathogenesis of this common cause of cognitive impairment in older persons, provide new opportunities in the diagnosis, early detection, and tracking of this disorder, and provide novel targets for the discovery of interventions to treat and prevent this disorder. Information about the genes that are preferentially expressed in relationship to normal neurological aging could provide new information about the molecular mechanisms that are involved in normal age-related cognitive decline and a host of age-related neurological disorders, and they could provide novel targets for the discovery of interventions to mitigate some of these deleterious effects.

Aim 1. Collect brain samples from three Alzheimer’s Disease Centers (ADCs) for subsequent gene expression profiling. Individuals will be stratified with respect to diagnostic groups (using both clinical and neuropathological criteria), age groups, and APOE genotype. 150 individual brains will be sampled from the Arizona ADC, the Duke University ADC, and the Washington University ADC. Miniscule sample sizes (200 um of sectioned tissue) from six brain regions that are histopathologically or metabolically relevant to AD and aging will be collected, ensuring that this proposal does not deplete the national resource. Frozen and fixed samples will be sent to Phoenix, sectioned in a standardized fashion, and then returned. Aim 2. Tissue heterogeneity will be eliminated prior to expression profiling by performing laser capture microscopy on all brain regions. Aim 3. Expression profile LCM-captured cells on the Affymetrix U133 Plus 2.0 array (~55,000 transcripts), and quickly provide these data to the community at large. Aim 4. Identify pathogenic cascades related to each of the clinico-pathologic correlates using unsupervised and supervised analyses coupled with a hypothesis-driven approach. Aim 5. Validation of the expression correlates at the protein and functional levels.

Scientific progress in the last few years has improved our understanding of AD and raised the hope of identifying treatments to halt the progression and prevent the onset of this disorder. For instance, researchers have begun to characterize the cascade of molecular events which lead to the major histopathological features of the disorder: neuritic plaques, which contain extra-cellular deposits of amyloid beta-peptides (Abeta); neurofibrillary tangles, which contain the hyperphosphorylated form of the intracellular, microtubule-associated protein, tau; and a loss of neurons and synapses. These molecular events provide targets for the development of promising new treatments. For example, A-beta has been postulated to trigger a cascade of events that are involved in the pathogenesis of AD. This proposal hopes to provide new information about the genes that are preferentially expressed in the development of AD histopathology, including the over-expression of APP, amyloid-induced neurotoxicity, and hyperphosphorylation of tau, as well as bring clarity to the metabolic abnormalities that seem to play a role in dementia and AD development and pathology.

We will perform LCM on 6 brain regions with about 14 biological replicates per brain region. The brain regions are as follows: 1) entorhinal cortex 2) hippocampus 3) medial temporal gyrus 4) posterior cingulate 5) superior frontal gyrus and 6) primary visual cortex. We will collect layer III pyramidal cells from the white matter in each region, isolate total RNA from LCMed cell lysates, and perform double round amplification of each sample for array analysis.

Bad arrays excluded: Four samples, highlighted in the table below, are bad arrays. For quality control, they should be excluded.

Index GEO Series Organ Region Tissue Case ID Age Sex 1 GSM119615 Entorhinal Cortex Normal E119615M63N 63 M 2 GSM119616 Entorhinal Cortex Normal E119616M85N 85 M 3 GSM119617 Entorhinal Cortex Normal E119617M80N 80 M 4 GSM119618 Entorhinal Cortex Normal E119618M->F80N 80 M 5 GSM119619 Entorhinal Cortex Normal E119619F->M102N 102 F 6 GSM119620 Entorhinal Cortex Normal E119620M79N 79 M 7 GSM119621 Entorhinal Cortex Normal E119621M76N 76 M 8 GSM119622 Entorhinal Cortex Normal E119622M83N 83 M 9 GSM119623 Entorhinal Cortex Normal E119623M79N 79 M 10 GSM119624 Entorhinal Cortex Normal E119624F88N 88 F 11 GSM119625 Entorhinal Cortex Normal E119625F82N 82 F 12 GSM119626 Entorhinal Cortex Normal E119626M69N 69 M 13 GSM119627 Entorhinal Cortex Normal E119627M78N 78 M 14 GSM238763 Entorhinal Cortex Alzheimer's E238763F82A 82 F 15 GSM238790 Entorhinal Cortex Alzheimer's E238790F86A 86 F 16 GSM238791 Entorhinal Cortex Alzheimer's E238791F93A 93 F 17 GSM238792 Entorhinal Cortex Alzheimer's E238792M84A 84 M 18 GSM238793 Entorhinal Cortex Alzheimer's E238793F79A 79 F 19 GSM238794 Entorhinal Cortex Alzheimer's E238794F78A 78 F 20 GSM238795 Entorhinal Cortex Alzheimer's E238795F91A 91 F 21 GSM238796 Entorhinal Cortex Alzheimer's E238796M86A 86 M 22 GSM238797 Entorhinal Cortex Alzheimer's E238797NA0A N/A N/A 23 GSM238798 Entorhinal Cortex Alzheimer's E238798M80A 80 M 24 GSM119628 Hippocampus Normal H119628M85N 85 M 25 GSM119629 Hippocampus Normal H119629M80N 80 M 26 GSM119630 Hippocampus Normal H119630M80N 80 M 27 GSM119631 Hippocampus Normal H119631F102N 102 F 28 GSM119632 Hippocampus Normal H119632M63N 63 M 29 GSM119633 Hippocampus Normal H119633M79N 79 M 30 GSM119634 Hippocampus Normal H119634M76N 76 M 31 GSM119635 Hippocampus Normal H119635M83N 83 M 32 GSM119636 Hippocampus Normal H119636M79N 79 M 33 GSM119637 Hippocampus Normal H119637F88N 88 F 34 GSM119638 Hippocampus Normal H119638F73N 73 F 35 GSM119639 Hippocampus Normal H119639M69N 69 M 36 GSM119640 Hippocampus Normal H119640M78N 78 M 37 GSM238799 Hippocampus Alzheimer's H238799F73A 73 F 38 GSM238800 Hippocampus Alzheimer's H238800M81A 81 M 39 GSM238801 Hippocampus Alzheimer's H238801M78A 78 M 40 GSM238802 Hippocampus Alzheimer's H238802M75A 75 M 41 GSM238803 Hippocampus Alzheimer's H238803F70A 70 F 42 GSM238804 Hippocampus Alzheimer's H238804F85A 85 F 43 GSM238805 Hippocampus Alzheimer's H238805F77A 77 F 44 GSM238806 Hippocampus Alzheimer's H238806M79A 79 M 45 GSM238807 Hippocampus Alzheimer's H238807M88A 88 M 46 GSM238808 Hippocampus Alzheimer's H238808M72A 72 M 47 GSM119641 Medial Temporal Gyrus Normal MT119641M85N 85 M 48 GSM119642 Medial Temporal Gyrus Normal MT119642M80N 80 M 49 GSM119643 Medial Temporal Gyrus Normal MT119643F102N 102 F 50 GSM119644 Medial Temporal Gyrus Normal MT119644M63N 63 M 51 GSM119645 Medial Temporal Gyrus Normal MT119645M79N 79 M 52 GSM119646 Medial Temporal Gyrus Normal MT119646M83N 83 M 53 GSM119647 Medial Temporal Gyrus Normal MT119647M79N 79 M 54 GSM119648 Medial Temporal Gyrus Normal MT119648F88N 88 F 55 GSM119649 Medial Temporal Gyrus Normal MT119649F82N 82 F 56 GSM119650 Medial Temporal Gyrus Normal MT119650F73N 73 F 57 GSM119651 Medial Temporal Gyrus Normal MT119651M69N 69 M 58 GSM119652 Medial Temporal Gyrus Normal MT119652M->F78N 78 M 59 GSM238809 Medial Temporal Gyrus Alzheimer's MT238809M81A 81 M 60 GSM238810 Medial Temporal Gyrus Alzheimer's MT238810M72A 72 M 61 GSM238811 Medial Temporal Gyrus Alzheimer's MT238811M75A 75 M 62 GSM238812 Medial Temporal Gyrus Alzheimer's MT238812M78A 78 M 63 GSM238813 Medial Temporal Gyrus Alzheimer's MT238813M75A 75 M 64 GSM238815 Medial Temporal Gyrus Alzheimer's MT238815F95A 95 F 65 GSM238816 Medial Temporal Gyrus Alzheimer's MT238816F81A 81 F 66 GSM238817 Medial Temporal Gyrus Alzheimer's MT238817F85A 85 F 67 GSM238818 Medial Temporal Gyrus Alzheimer's MT238818M79A 79 M 68 GSM238819 Medial Temporal Gyrus Alzheimer's MT238819F82A 82 F 69 GSM238820 Medial Temporal Gyrus Alzheimer's MT238820M88A 88 M 70 GSM238821 Medial Temporal Gyrus Alzheimer's MT238821M72A 72 M 71 GSM238822 Medial Temporal Gyrus Alzheimer's MT238822F73A 73 F 72 GSM238823 Medial Temporal Gyrus Alzheimer's MT238823M87A 87 M 73 GSM238824 Medial Temporal Gyrus Alzheimer's MT238824M68A 68 M 74 GSM238825 Medial Temporal Gyrus Alzheimer's MT238825F80A 80 F 75 GSM119653 Posterior Cingulate Normal PC119653M85N 85 M 76 GSM119654 Posterior Cingulate Normal PC119654M80N 80 M 77 GSM119655 Posterior Cingulate Normal PC119655F102N 102 F 78 GSM119656 Posterior Cingulate Normal PC119656M63N 63 M 79 GSM119657 Posterior Cingulate Normal PC119657M79N 79 M 80 GSM119658 Posterior Cingulate Normal PC119658M->F76N 76 M 81 GSM119659 Posterior Cingulate Normal PC119659M83N 83 M 82 GSM119660 Posterior Cingulate Normal PC119660M79N 79 M 83 GSM119661 Posterior Cingulate Normal PC119661F88N 88 F 84 GSM119662 Posterior Cingulate Normal PC119662F82N 82 F 85 GSM119663 Posterior Cingulate Normal PC119663F73N 73 F 86 GSM119664 Posterior Cingulate Normal PC119664M69N 69 M 87 GSM119665 Posterior Cingulate Normal PC119665M78N 78 M 88 GSM238826 Posterior Cingulate Alzheimer's PC238826F73A 73 F 89 GSM238827 Posterior Cingulate Alzheimer's PC238827M81A 81 M 90 GSM238834 Posterior Cingulate Alzheimer's PC238834M78A 78 M 91 GSM238835 Posterior Cingulate Alzheimer's PC238835M75A 75 M 92 GSM238837 Posterior Cingulate Alzheimer's PC238837M68A 68 M 93 GSM238838 Posterior Cingulate Alzheimer's PC238838F70A 70 F 94 GSM238839 Posterior Cingulate Alzheimer's PC238839F85A 85 F 95 GSM238840 Posterior Cingulate Alzheimer's PC238840M79A 79 M 96 GSM238841 Posterior Cingulate Alzheimer's PC238841M88A 88 M 97 GSM119666 Superior Frontal Gyrus Normal SF119666M79N 79 M 98 GSM119667 Superior Frontal Gyrus Normal SF119667F->M88N 88 F 99 GSM119668 Superior Frontal Gyrus Normal SF119668F->M82N 82 F 100 GSM119669 Superior Frontal Gyrus Normal SF119669F->M73N 73 F 101 GSM119670 Superior Frontal Gyrus Normal SF119670F->M102N 102 F 102 GSM119671 Superior Frontal Gyrus Normal SF119671M63N 63 M 103 GSM119672 Superior Frontal Gyrus Normal SF119672M->F79N 79 M 104 GSM119673 Superior Frontal Gyrus Normal SF119673M->F76N 76 M 105 GSM119674 Superior Frontal Gyrus Normal SF119674M->F83N 83 M 106 GSM119675 Superior Frontal Gyrus Normal SF119675M69N 69 M 107 GSM119676 Superior Frontal Gyrus Normal SF119676M78N 78 M 108 GSM238842 Superior Frontal Gyrus Alzheimer's SF238842F73A 73 F 109 GSM238843 Superior Frontal Gyrus Alzheimer's SF238843M81A 81 M 110 GSM238844 Superior Frontal Gyrus Alzheimer's SF238844M72A 72 M 111 GSM238845 Superior Frontal Gyrus Alzheimer's SF238845M75A 75 M 112 GSM238846 Superior Frontal Gyrus Alzheimer's SF238846M78A 78 M 113 GSM238847 Superior Frontal Gyrus Alzheimer's SF238847M75A 75 M 114 GSM238848 Superior Frontal Gyrus Alzheimer's SF238848M87A 87 M 115 GSM238851 Superior Frontal Gyrus Alzheimer's SF238851F95A 95 F 116 GSM238854 Superior Frontal Gyrus Alzheimer's SF238854M68A 68 M 117 GSM238855 Superior Frontal Gyrus Alzheimer's SF238855F95A 95 F 118 GSM238856 Superior Frontal Gyrus Alzheimer's SF238856F70A 70 F 119 GSM238857 Superior Frontal Gyrus Alzheimer's SF238857F85A 85 F 120 GSM238858 Superior Frontal Gyrus Alzheimer's SF238858F83A 83 F 121 GSM238860 Superior Frontal Gyrus Alzheimer's SF238860F77A 77 F 122 GSM238861 Superior Frontal Gyrus Alzheimer's SF238861F83A 83 F 123 GSM238862 Superior Frontal Gyrus Alzheimer's SF238862M68A 68 M 124 GSM238863 Superior Frontal Gyrus Alzheimer's SF238863M79A 79 M 125 GSM238864 Superior Frontal Gyrus Alzheimer's SF238864F82A 82 F 126 GSM238865 Superior Frontal Gyrus Alzheimer's SF238865M88A 88 M 127 GSM238867 Superior Frontal Gyrus Alzheimer's SF238867F80A 80 F 128 GSM238868 Superior Frontal Gyrus Alzheimer's SF238868M74A 74 M 129 GSM238870 Superior Frontal Gyrus Alzheimer's SF238870M72A 72 M 130 GSM238871 Superior Frontal Gyrus Alzheimer's SF238871M80A 80 M 131 GSM119677 Primary Visual Cortex Normal V119677M85N 85 M 132 GSM119678 Primary Visual Cortex Normal V119678M80N 80 M 133 GSM119679 Primary Visual Cortex Normal V119679M63N 63 M 134 GSM119680 Primary Visual Cortex Normal V119680M79N 79 M 135 GSM119681 Primary Visual Cortex Normal V119681M76N 76 M 136 GSM119682 Primary Visual Cortex Normal V119682M83N 83 M 137 GSM119683 Primary Visual Cortex Normal V119683M79N 79 M 138 GSM119684 Primary Visual Cortex Normal V119684F88N 88 F 139 GSM119685 Primary Visual Cortex Normal V119685F82N 82 F 140 GSM119686 Primary Visual Cortex Normal V119686F73N 73 F 141 GSM119687 Primary Visual Cortex Normal V119687M69N 69 M 142 GSM119688 Primary Visual Cortex Normal V119688M78N 78 M 143 GSM238872 Primary Visual Cortex Alzheimer's V238872F73A 73 F 144 GSM238873 Primary Visual Cortex Alzheimer's V238873M81A 81 M 145 GSM238874 Primary Visual Cortex Alzheimer's V238874M75A 75 M 146 GSM238875 Primary Visual Cortex Alzheimer's V238875M78A 78 M 147 GSM238877 Primary Visual Cortex Alzheimer's V238877M75A 75 M 148 GSM238941 Primary Visual Cortex Alzheimer's V238941M87A 87 M 149 GSM238942 Primary Visual Cortex Alzheimer's V238942F95A 95 F 150 GSM238943 Primary Visual Cortex Alzheimer's V238943M68A 68 M 151 GSM238944 Primary Visual Cortex Alzheimer's V238944F70A 70 F 152 GSM238945 Primary Visual Cortex Alzheimer's V238945F81A 81 F 153 GSM238946 Primary Visual Cortex Alzheimer's V238946F85A 85 F 154 GSM238947 Primary Visual Cortex Alzheimer's V238947M68A 68 M 155 GSM238948 Primary Visual Cortex Alzheimer's V238948M79A 79 M 156 GSM238949 Primary Visual Cortex Alzheimer's V238949F82A 82 F 157 GSM238951 Primary Visual Cortex Alzheimer's V238951M88A 88 M 158 GSM238952 Primary Visual Cortex Alzheimer's V238952M74A 74 M 159 GSM238953 Primary Visual Cortex Alzheimer's V238953M72A 72 M 160 GSM238955 Primary Visual Cortex Alzheimer's V238955M->F68A 68 M 161 GSM238963 Primary Visual Cortex Alzheimer's V238963F80A 80 F

Experiment design

Human brain expression data in patients with Alzheimer's disease and age-matched elderly control subjects. This cortical expression data set is taken from GEO GSE5281 (Liang et al. 2006, Liang et al. 2008). Samples were laser-captured from cortical regions of 16 normal elderly humans (10 males and 4 females) and from 33 AD cases (15 males and 18 females). Mean age of cases and controls was 80 years. All samples were run on the Affymetrix U133 Plus 2.0 array. We renormalized the RMA data to an average expression of 8 units on a log2 scale. Two versions of the data have been entered in GeneNetwork: one consisting of 157 of 161 arrays (full set minus 4 arrays we consider of poor quality); the second consisting of what we regard as the best 102 arrays (those with mean correlations of better than 0.88 with all other arrays). Case IDs have the following code structure: Brain Region, GEO ID, Sex, Age, Disease Status. E119615M63N is a sample of the entorhinal cortex of case GSM119615, a male 63 year old normal case. The tissue codes are E = enorhinal cortex layer II, H = hippocampus CA1 pyramidal layer, MT = medial temporal cortex layer III, PC = porterior cingulate cortex layer III, SP = supeior frontal cortex layer III, V = primary visual cortex area 17 layer III. GeneNetwork does not yet allow sophisticated display of the data, but you can perform correlation analyses of any of the 56,000 probe sets. For example, expression of the APP transcript is higher in the AD cases and correlates well with many other AD related genes.

NOTE: We detected a minimum of 7.6% case assignment error rate (12 of 158 arrays) in this data set. Twelve cases are assigned to the wrong sex (see XIST probe set 224588_at, the figure below, and table 1). This raises the possibility that some cases are also misassigned by cortical brain region and disease status.

 

Legend: Expression of the sex-specific gene XIST reveals about 10 sex assignment errors in this data set.

Samples were laser-captured from cortical layer 3 (except the hippocampus) and run on the Affymetrix U133 Plus 2.0 array. We renormalized the data to an average expression of 8 units on a log2 scale. Case IDs have the following code structure: Brain Region, GEO ID, Sex, Age, Disease Status. E119615M63N is a sample of the entorhinal cortex of case GSM119615, a male 63 year old normal case. The tissue codes are E = enorhinal cortex layer II, H = hippocampus CA1 pyramidal layer, MT = medial temporal cortex layer III, PC = porterior cingulate cortex layer III, SP = supeior frontal cortex layer III, V = primary visual cortex layer III. A total of 16 normal subjects were used (10 M and 4 female). The AD samples. GeneNetwork does not allow sophisticated display of the data, but you can perform correlation analyses of any of the 56,000 probe sets. For example expression of the APP transcript is higher in the AD cases and correlates well with many other AD related genes.

Information about the genes that are preferentially expressed during the course of Alzheimer's disease (AD) could improve our understanding of the molecular mechanisms involved in the pathogenesis of this common cause of cognitive impairment in older persons, provide new opportunities in the diagnosis, early detection, and tracking of this disorder, and provide novel targets for the discovery of interventions to treat and prevent this disorder. Information about the genes that are preferentially expressed in relationship to normal neurological aging could provide new information about the molecular mechanisms that are involved in normal age-related cognitive decline and a host of age-related neurological disorders, and they could provide novel targets for the discovery of interventions to mitigate some of these deleterious effects.

About platform

Affymetrix submissions are typically submitted to GEO using the GEOarchive method described at http://www.ncbi.nlm.nih.gov/projects/geo/info/geo_affy.html Complete coverage of the Human Genome U133 Set plus 6,500 additional genes for analysis of over 47,000 transcripts All probe sets represented on the GeneChip Human Genome U133 Set are identically replicated on the GeneChip Human Genome U133 Plus 2.0 Array. The sequences from which these probe sets were derived were selected from GenBank®, dbEST, and RefSeq. The sequence clusters were created from the UniGene database (Build 133, April 20, 2001) and then refined by analysis and comparison with a number of other publicly available databases, including the Washington University EST trace repository and the University of California, Santa Cruz Golden-Path human genome database (April 2001 release).

In addition, there are 9,921 new probe sets representing approximately 6,500 new genes. These gene sequences were selected from GenBank, dbEST, and RefSeq. Sequence clusters were created from the UniGene database (Build 159, January 25, 2003) and refined by analysis and comparison with a number of other publicly available databases, including the Washington University EST trace repository and the NCBI human genome assembly (Build 31).

Contributors

Stephan DA, Liang WS

Citation

Liang WS, Dunckley T, Beach TG, Grover A et al. Gene expression profiles in anatomically and functionally distinct regions of the normal aged human brain. Physiol Genomics 2007 Feb 12;28(3):311-22. PMID: 17077275
Liang WS, Reiman EM, Valla J, Dunckley T et al. Alzheimer's disease is associated with reduced expression of energy metabolism genes in posterior cingulate neurons. Proc Natl Acad Sci U S A 2008 Mar 18;105(11):4441-6. PMID: 18332434

Acknowledgment

Please cite: Liang WS, Reiman EM, Valla J, Dunckley T, Beach TG, Grover A, Niedzielko TL, Schneider LE, Mastroeni D, Caselli R, Kukull W, Morris JC, Hulette CM, Schmechel D, Rogers J, Stephan DA (2008) Alzheimer's disease is associated with reduced expression of energy metabolism genes in posterior cingulate neurons. Proc Natl Acad Sci USA 105:4441-4446.