Alzheimer’s Disease

1. Alzheimer’s Disease BRAIN, THE FINAL FRONTIER Kiminobu Sugaya, Ph.D.

2. Alzheimer’s Disease

3. NH2 COOH A Plaques Normal Secretory Pathway Amyloid-b precursor protein b-secretase -secretase g-secretase -amyloid deposition

4. Mechanism of Neurodegeneration in Alzheimer’s Disease APP Glial Activation Presenilin Presenilin Ab 1-40, 1-42 Neurodegeneration Amyloid Deposition

5. Glial Activation in Aging and Disease Neuronal Dysfunction or Neurodegeneration Glial Activation (Inflammation) Shift Shift Age

6. DNA Fragmentation Cromatin Condensation Membrane Blebbing and Loss of Nuclear Envelope Cellular Fragmentation into Apoptotic Bodies APOPTOSIS APOPTOSIS Phagocytosis and Degradation

7. Alzheimer’s disease Fragmented DNA (Apoptosis) in the hippocampus Aged Control

8. Plaque with many Plaque with many TUNEL positive TUNEL positive cells cells Plaque with no Plaque with no TUNEL positive TUNEL positive cells cells Plaque with a few TUNEL positive cells Plaque with a few TUNEL positive cells Amyloid Plaque and Apoptosis

9. Neuro-fibrillary Tangles and Apoptosis

10. Apoptotic Cells Astorocyte Astrocyte and Apoptosis

11. Ci/g tissue 14.68 68.42 122.16 175.90 229.64 283.38 337.13 390.87 444.61 600 Young 498.35 552.09 605.83 young 500 659.57 Aged unimpaired 713.31 Aged impaired 767.05 820.79 400 874.54 928.28 982.02 300 1035.76 Radio activity in the section (nCi/g) 1089.50 1 1 4 3 . 2 4 Aged unimpaired 1 1 9 6 . 9 8 200 1250.72 p=0.0001 1304.46 1358.20 100 1 4 1 1 . 9 4 1465.69 1519.43 0 1573.17 1626.91 300 120 140 160 180 200 220 240 260 280 1680.65 1734.39 memory score Aged impaired Regression Analysis of GFAP mRNA Expression in the Hippocampus against the Memory Score GFAP mRNA Expression in the Aged Memory Impaired Model Rat

12. 68.17 176.38 284.60 392.81 501.03 609.24 717.46 825.67 933.89 1042.10 1 150.31 1258.53 1366.74 young 2000 1474.96 Aged unimpaired 1583.17 Aged impaired 1900 1691.39 1799.60 1800 1907.81 1700 2016.03 2124.24 1600 2232.46 Radio activity in the section (nCi/g) 2340.67 1500 2448.89 1400 2557.10 2665.32 1300 2773.53 2881.74 1200 p = 0.0055 2989.96 1100 3098.17 3206.39 3314.60 3422.82 120 140 160 180 200 220 240 260 280 300 3531.03 memory score Ci/g tissue Regression Analysis of APP mRNA Expression in the Hippocampus against the Memory Score APP mRNA Expression in the Aged Memory Impaired Model Rat Young Aged unimpaired Aged impaired

13. 210 young Aged unimpaired 190 Aged impaired 170 150 Radio activity in the section (nCi/g) 130 110 p = 0.0190 90 120 140 160 180 200 220 240 260 280 300 memory score Ci/g tissue Regression Analysis of Mn-SOD mRNA Expression in the Hippocampus against the Memory Score 49.28 52.13 54.97 57.82 60.66 63.51 66.36 69.20 72.05 74.89 77.74 80.59 83.43 86.28 89.12 91.97 94.82 97.66 100.51 103.35 106.20 109.04 111.89 114.74 117.58 120.43 123.27 126.12 128.97 131.81 134.66 137.50 Mn-SOD mRNA Expression in the Aged Memory Impaired Model Rat Young Aged unimpaired Aged impaired

14. Hilus CA1 Dentate Gyrus CA1 Dentate Gyrus Hilus APP ISHH with GFAP Immunostaining in the Aged Memory Impaired Model Rats Aged Impaired matured

15. GFAP ISHH (astrocytes marker) with 4G8 (Ab) Immuno-histochemistry in PS1-APP TM

16. APP ISHH with 4G8 (Ab) Immuno-histochemistry in PS1-APP TM APP ISHH with GFAP Immuno-histochemistry (astrocytes marker) in PS1-APP TM