By: Hayley Elia

 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

 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

 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

 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

 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

 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

 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

 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.

 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

 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)

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