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. 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. 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. Amyloid Beta Induces Rapid Degradation of Full Length Tau

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. 50 - 75% Corresponding Neuronal Viability Protease Activity Tau Degradation

7. Activation of Tau Targeting Kinases GSK3  CDK-5

8. Tau Phosphorylation Changes?

11. Cairns et al., Journal of Pathology V-204 P-438 2004 Extra Slide -Tau Related Diseases xxxxxx

12. Extra Slide - Protease Assays

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)

14. Extra Slide - ERK / AKT Signaling