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Molecular Signatures in Post-Mortem Brain Tissue of Younger Alzheimer’s Disease Risk Individuals

This study investigates the molecular signatures in post-mortem brain tissue from younger individuals genetically at high risk for Alzheimer’s disease (AD) based on APOE genotype. By analyzing cortical tissue from APOE4 carriers and non-carriers, researchers identified significant differences in gene expression, highlighting neuroprotective factors and signaling pathway disruptions. The findings indicate that early signs of AD pathogenesis are associated with specific abnormalities in biological signaling processes in the brain, providing insight into potential therapeutic targets and preventative strategies.

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Molecular Signatures in Post-Mortem Brain Tissue of Younger Alzheimer’s Disease Risk Individuals

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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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