GAB2 Alleles Modify Alzheimer's Risk in APOE ɛ4 Carriers

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GAB2 Alleles Modify Alzheimer's Risk in APOE ɛ4 Carriers Eric M. Reiman, Jennifer A. Webster, Amanda J. Myers, John Hardy, Travis Dunckley, Victoria L. Zismann, Keta D. Joshipura, John V. Pearson, Diane Hu-Lince, Matthew J. Huentelman, David W. Craig, Keith D. Coon, Winnie S. Liang, RiLee H. Herbert, Thomas Beach, Kristen C. Rohrer, Alice S. Zhao, Doris Leung, Leslie Bryden, Lauren Marlowe, Mona Kaleem, Diego Mastroeni, Andrew Grover, Christopher B. Heward, Rivka Ravid, Joseph Rogers, Michael L. Hutton, Stacey Melquist, Ron C. Petersen, Gene E. Alexander, Richard J. Caselli, Walter Kukull, Andreas Papassotiropoulos, Dietrich A. Stephan Neuron Volume 54, Issue 5, Pages 713-720 (June 2007) DOI: 10.1016/j.neuron.2007.05.022 Copyright © 2007 Elsevier Inc. Terms and Conditions

Figure 1 Linkage Disequilibrium Structure and Haplotype Significance Levels for the Region Encompassing GAB2 Plots follow the Haploview GOLD heatmap color scheme. SNP numbers correspond to the following dbSNP ID identification numbers: 1:rs579711, 2:rs977978, 3:rs637149, 4:rs977977, 5:rs901104, 6:rs1385600, 7:rs11237419, 8:rs1007837, 9:rs2450130, 10:rs2510054, 11:rs11237429, 12:rs2510038, 13:rs2511170, 14:rs4945261, 15:rs7101429, 16:rs10793294, 17:rs4291702, 18:rs11602622, 19:rs10899467, 20:rs2458640, 21:rs10793302, 22:rs2373115, 23:rs12280198, 24:rs12287010, 25:rs17136630, 26:rs4945276, 27:rs1996172, 28:rs7395344, 29:rs11237522, and 30:rs7950813. In all three cohorts, there was a GAB2 risk haplotype, a protective haplotype, and a haplotype unrelated to LOAD risk in APOE ɛ4 carriers. Neuron 2007 54, 713-720DOI: (10.1016/j.neuron.2007.05.022) Copyright © 2007 Elsevier Inc. Terms and Conditions

Figure 2 siRNA Knockdown of GAB2 Increases Tau Phosphorylation In comparison with vehicle treatment (red, upper left), GAB2 siRNA treatment resulted in a 1.70-fold increase in tau phosphorylation at the serene-262 residue (red, lower left), which is phosphorylated in LOAD neurofibrillary tangle-bearing neurons. This fold-change was not attributable to an increase in total tau (green, upper and lower right). Neuron 2007 54, 713-720DOI: (10.1016/j.neuron.2007.05.022) Copyright © 2007 Elsevier Inc. Terms and Conditions

Figure 3 Gab2 Colocalizes with Dystrophic Neurons in the AD Brain (A) LOAD hippocampus (neutral red counterstain) (40× objective). The arrow indicates a highly dystrophic cell with the size and morphology of a cortical pyramidal neuron. Arrowheads point to one of many structures in the sections that resemble dystrophic neurites or neuropil threads. (B) LOAD hippocampus (neutral red counterstain) (40×). The arrow denotes a putative neurofibrillary tangle-containing neuron. Arrowheads again indicate a dystrophic neurite. (C) LOAD posterior cingulate gyrus (40×). Filled arrows point to normal-appearing putative neurons. The open arrow points to a cell with the features of a neurofibrillary tangle-bearing neuron. Immunoreactive structures clearly resembling pyramidal cell apical dendrites were also observed ascending through the cortical layers (arrowheads). (D) LOAD posterior cingulate cortex (100× objective). Shown is a Gab2 immunoreactive cell with the flame-shaped cytoplasmic inclusion typical of the neurofibrillary tangle. Neuron 2007 54, 713-720DOI: (10.1016/j.neuron.2007.05.022) Copyright © 2007 Elsevier Inc. Terms and Conditions