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1. Introduction
2. Alois Alzheimer
3. The amyloid plaque
4. Amyloid congophilic angiopathy (ACA)
5. Impact of delaying onset of AD
6. Impact of delayed onset on prevalence of AD
7. The amyloidocentric theory of AD
8. Alzheimer's disease - some hard facts
9. Alzheimer's disease - some soft facts
10. Compelling evidence for the Abeta theory of AD
11. Attempting to modify AD and delay its onset
12. Optional targets for a disease-modifying drug
13. APP structure and domains
14. Conformation of APP dimers
15. Iron-export ferroxidase activity of APP
16. FAD APP mutations cluster sites
17. Age at onset correlates with Abeta isoforms
18. Reconstituting gamma-secretase activity
19. Activation of PS1
20. Discovering the oligomers of Abeta
21. Abeta amyloid
22. P3 oligomer crystal structure (1)
23. P3 oligomer crystal structure (2)
24. P3 oligomer crystal structure (3)
25. P3 oligomer crystal structure (4)
26. Abeta pleotropic high-affinity Cu-II binding sites
27. The mechanism of neurodegeneration
28. The physical state of Abeta amyloid
29. Current working model of Abeta toxicity
30. Soluble/insoluble Abeta: SDS-resistant oligomers
31. Abeta doesn't aggregate in the absence of metals
32. Abeta metal binding modes
33. Abeta insertion into membrane - a model
34. Hydrogen peroxide generation by beta-amyloid
35. H2O2 required to generate Abeta oligomers
36. Abeta binds to lipid headgroups
37. Synapse binding of Abeta pivotal for toxicity
38. Detecting Abeta species binding to lipids
39. Annexin inhibition of Abeta-lipid binding
40. Toxicity of L- and D-Abeta42
41. Cell binding of L- and D-Abeta42
42. Annexin V inhibits cell binding of L-Abeta
43. Abeta - current model
44. Model - MPAC with moderate affinity for metals
45. Clioquinol (CQ, PBT1) the prototypic MPAC
46. Clioquinol prevents Cu(II) interaction with Abeta
47. Effect of MPAC (CQ) on Abeta load
48. CQex ADAS-cog change from baseline
49. PBT2: SAR based on rational drug design
50. PBT2 is equal to or better than CQ
51. PBT2 inhibits oxidative oligomerization of Abeta
52. Effect of PBT2 on interstitial Abeta levels
53. Effect of PBT2 on Abeta inhibition of LTP
54. Effect of PBT2 on CA1 dendritic spine density
55. Functional effect of PBT2 on APP/PS1 mice
56. PBT2 reduces Abeta species in the brain
57. Short-term PBT2 treatment of female APP/PS1
58. PBT2 increases synaptophysin levels in mice
59. CQ (PBT1) vs. PBT2
60. Study of PBT2-multicentered, placebo-controlled
61. Effect of PBT2 on levels of biomarkers
62. PBT2 effect on the change from pretreatment
63. AD Abeta-directed therapeutics - drugs
64. AD Abeta-directed therapeutics - biologics
65. Phase II results of potential Abeta targeting drugs
66. Phase II results of 'failed' Abeta targeting drugs
67. Platinum complexes

Topics Covered

• The amyloid plaque
• Impact of delaying onset of AD
• The amyloidocentric theory of Alzheimer's disease
• Compelling evidence for the Abeta theory of AD
• Delay onset of AD by 5 years
• The best target for a disease-modifying drug
• APP structure and domains
• Iron-export ferroxidase activity of beta-amyloid precursor protein
• Age at onset correlates with Abeta isoforms
• Activation of PS1
• Abeta amyloid
• The mechanism of neurodegeneration
• Abeta metal binding modes
• Current working model of Abeta toxicity
• Abeta amyloid protein: current model consistent with EXAFS
• Metal-protein attenuating compound (MPAC) with moderate affinity for metals
• Clioquinol (CQ, PBT1) the prototypic MPAC
• PBT2: SAR based on rational drug design
• CQ (PBT1) vs. PBT2
• Alzheimer's disease Abeta-directed therapeutics in clinical development: drugs and biologics
• Phase II results of Abeta targeting AD modifying drugs

Links

Series:

• Alzheimer's Disease
• Drug Discovery and Development in the Neurosciences

Categories:

• Clinical Practice
• Neuroscience

Therapeutic Areas:

• Neurology

Talk Citation

Publication History

• Published on October 27, 2011

Financial Disclosures

• Prof. Colin L. Masters has not informed HSTalks of any commercial/financial relationship that it is appropriate to disclose.