Neuroscience Retreat 2009

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Neuroscience Retreat 2009

  1. 1. Jack Reifert, DeeAnn Hartung, Stuart Feinstein Neurons in Distress – Linking Amyloid Beta Induced Stress on Hippocampal Neurons to Tau Biochemistry Annual NRI Retreat - 2009
  2. 2. Disease Related Changes to MAPT (Tau) N C 441 1 Microtubule Binding Domains Accumulation of NFT’s: - Fragmentation - Hyperphosphorylation - Aggregation 45 74 103 Nature Medicine   10 , 1055 - 1063 (2004) Eckhard Mandelkow et al., Brain Pathology 17 (1) , 83–90 , January 2007 257 11 44 230 254 267 310 340 394 Potential Calpain Cleavage Sites
  3. 3. Amyloid Beta Pathology in Alzheimer’s Disease Nature Medicine   10 , 1055 - 1063 (2004) AICD Extracellular Domain Amyloid Precursor Protein (APP)   Amyloid-  Insoluble Fibers / Plaques Soluble Oligomers
  4. 4. Amyloid Beta Induces Rapid Degradation of Full Length Tau
  5. 5. Protease Mediated Tau Degradation? 35 kD 25 kD 5 Min 10 Min 15 Min 30 Min 1 Hour 2 Hour 150% 475% 325% 250% 225% 140% Time: % Calpain Activity: Tau GAPDH % Caspase Activity: 160% 150% 135% 120% 45% 40% 4 Hour 75% 20%
  6. 6. 50 - 75% Corresponding Neuronal Viability Protease Activity Tau Degradation
  7. 7. Activation of Tau Targeting Kinases GSK3  CDK-5
  8. 8. Tau Phosphorylation Changes?
  9. 10. Summary: <ul><li>Tau degradation precedes cell death. </li></ul><ul><li>While full length tau disappears, </li></ul><ul><li>low MW tau fragments are retained. </li></ul><ul><li>Survival signaling cascades are perturbed </li></ul><ul><li>by amyoid beta treatment resulting in GSK3  </li></ul><ul><li>kinase activation. </li></ul><ul><li>Protease activation by amyloid beta may be </li></ul><ul><li>responsible for tau degradation and CDK-5 </li></ul><ul><li>activation. </li></ul><ul><li>Phospho-specific tau epitopes are detected </li></ul><ul><li>robustly in untreated samples, and no increase </li></ul><ul><li>is seen with amyloid beta treatment. </li></ul>
  10. 11. Cairns et al., Journal of Pathology V-204 P-438 2004 Extra Slide -Tau Related Diseases xxxxxx
  11. 12. Extra Slide - Protease Assays
  12. 13. Extra Slide - ATP Cell Viability Concentration of Amyloid Beta (  M) Percent Cell Death Time of Amyloid Beta Treatment ATP Luminescent Cell Viability Assay (Cell-Titer Glow® - Promega # G7570)
  13. 14. Extra Slide - ERK / AKT Signaling

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