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By: Hayley Elia

Molecular signatures in post-mortem brain tissue of younger individuals at high risk for Alzheimer’s disease as based on APOE genotype. By: Hayley Elia. What is Alzheimer’s Disease?. Neurodegenerative disorder in which nerve cells in the brain die

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By: Hayley Elia

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  1. Molecular signatures in post-mortem brain tissue of younger individuals at high risk for Alzheimer’s disease as based on APOE genotype By: Hayley Elia

  2. What is Alzheimer’s Disease? • Neurodegenerative disorder in which nerve cells in the brain die • Symptoms include short-term memory loss, difficulty performing familiar tasks, disorientation, and trouble with language • Late onset AD (LOAD) affects approximately 1 in 10 people over the age 65

  3. Apolipoprotein E • Class of apolipoprotein that binds to a specific receptor on liver cells and peripheral cells • Essential for normal catabolism of triglyceride-rich lipoprotein constituents • E4 variant is the largest known genetic risk factor for LOAD • AD is characterized by build-ups of aggregates of peptide beta-amyloid; APOE enhances the proteolytic break-down of this peptide • Some forms of APOE are not as efficient at fulfilling these reactions

  4. Molecular signatures in post-mortem brain tissue of younger individuals at high risk for Alzheimer’s disease as based on APOE genotypeConejero-Goldberg, et al. 2011 • Transcriptional profiling study • Purpose was to identify neurosusceptibility and intrinsic neuroprotective factors, without the confounding factors of pathology • Studied post-mortem cortical tissue of 13 carriers and 28 non-carriers of the APOE4 genotype • APOE3 group=low risk group; APOE4 group=high risk group

  5. Obtaining Tissue Samples • Brain tissue obtained from the Clinical Brain Disorders Branch of the NIMH • Gray matter from BA 21 and BA 1/2/3 obtained from each subject using a high-speed hand-held dental drill • Tissue samples from frozen blocks pulverized and total RNA extracted • RNA converted to cDNA by reverse transcription using ArrayScript reverse transcriptase and T7-oligo primers, followed by second-strand synthesis • cDNA hybridized to the microarray platform and stained for visualization

  6. Identification of Transcripts • Interregional difference scores in gene expression between cortical tissue from a region invulnerable to AD (primary somatosensory cortex, BA 1/2/3) and an area susceptible to AD pathology (middle temporal gyrus, BA 21) • After contrasting the interregional differences, 70 transcripts that differed between APOE3 and APOE4 groups were identified • Transcripts included: EGFR, CNTFR, CASP6, GRIA2, CTNNB1, FKBPL, LGALS1, PSMC5

  7. Cluster Analysis of Identified Transcripts • Cluster analysis conducted using the average distance method of the signal intensity values of the 70 gene transcripts identified • Four clusters determined • In clusters 1 and 4, APOE4 BA 21 signal intensities were upregulated, while in clusters 2 and 3, they were downregulated • APOE4 BA 1/2/3 values were upregulated in clusters 2 and 3 and downregulated in clusters 1 and 4- reciprocal relationship to BA 21 findings; could possibly indicate regionally specific neuroprotective adaptations • Modal pattern, which contained the largest number of transcripts, was Cluster 1, in which BA 21 transcripts genes were upregulated and BA 1/2/3 transcripts were downregulated

  8. Regional Differences in APOE Expression • In the majority of cases in the APOE4 group, about 55% of the significant transcripts identified demonstrated interregional differences in expression, which were associated with strong upregulation in BA 21 lobe and downregulation in BA 1/2/3 • APOE3 group demonstrated a less distinct pattern of upregulation and downregulation

  9. Disruption of Biological and Signaling Pathways • 22 pathways differed between the APOE3 and APOE4 groups • A variety of abnormalities in signaling cascades and biological processes identified • Pathways included several of the pathways that have been implicated in previous studies of AD, including wnt signaling, calcium signaling, cell cycle, insulin signaling, etc.

  10. RT-qPCR • Microarray findings were validated in 9 transcripts chosen from 70 transcripts identified • Transcripts chosen on basis of statistical significance, role in key biological/signaling pathways, and relevance to AD pathogenesis • Results were consistent with microarray results in terms of regional up- or down- regulation for APOE3 and APOE4 groups

  11. Concluding Findings • Earliest traces of pathogenesis for AD in APOE4 individuals may be found in a number of abnormalities in signaling cascades and biological processes • Protective processes as well as pathological processes may be present (as indicated by clustering patterns) • Lower levels of APOE transcript were detected in the BA 1/2/3 region than in the BA 21 region (even in APOE4 carriers)

  12. Sources • http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2953572/?tool=pubmed#SD1 • http://www.webmd.com/alzheimers/guide/alzheimers-basics

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