Successfully reported this slideshow.
We use your LinkedIn profile and activity data to personalize ads and to show you more relevant ads. You can change your ad preferences anytime.

Neuroscience Retreat 2009

496 views

Published on

  • Be the first to comment

  • Be the first to like this

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

×