Key Issues in pharmacotherapy of β -amyloid

1. Key Issues in pharmacotherapy of β-amyloid Anujkumar Shah Jonathon Sun Simon Tran Taleen Karneig PHM142 Fall 2013 Coordinator: Dr. Jeffrey Henderson Instructor: Dr. David Hampson

2. What is β-amyloid? • A 4kDa peptide • Cleavage product of the amyloid precursor protein (APP) • Two membrane-bound endoprotease • β- and γ-secretase • Normal function is not well understood • No loss of function in animals

3. APP cleavage

4. The Role of Metals in β-amyloid aggregations

5. Associated Diseases • Alzheimer’s Disease (AD) • Amyloid hypothesis-Accumulation of β-amyloid in brain (amyloid plaques) resulting in disruption of nerve fibers • Genetically engineered mice that carry genes linked to Alzheimer’s diseases develop amyloid plaques and mimic symptoms of human Alzheimer’s • Other hypothesis- Cholinergic and Tau Hypotheses

6. Plaque formation Oligomers Fibrillin β-sheets Plaques

7. Strategies for Drug Targets Decrease production of β-amyloid Prevent/reduce aggregation of β-amyloid which may prevent the formation of amyloid plaque Increase the elimination of β-amyloid from the brain

8. Potential targets for decreasing production of β-amyloid • Secretases involved in cutting of the APP • Inhibitors block the clipping action of the secretases • Could prevent/reduce production of β-amyloid • Ex. LY-450139 (Semagacestat) γ-secretase inhibitor • Increase activation of secretases that cut APP into other products other than β-amyloid • Ex. R-fluriprofen -secretase modulator

9. New Drugs in Development • PBT2

10. Alzhemed • Also called tramiprosate or homotaurine. • It failed because it did not pass phase 3 trials. • How it is supposed to work? • GAGs bind to β-amyloid, and make itmore fibrillogenic, promoting formation of random-coil to Beta-sheet. • The β-sheet protects β-amyloid from proteolysis. • Tramiprosate is a glycosaminoglycan (GAG) mimetic, by mimicking ionic properties of GAGs. • It also passes the blood-brain barrier due to its low molecular weight. • Tramiprosate binding is supposed to be anti-fibrillogenic, reducing toxicity.

11. Immune Response to β-amyloid • ACC-001 • “active” vaccine • Inject β-amyloid fragments attached to carrier proteins • Using a surface-active saponin adjuvant QS-21 to help induce immune response • Antibodies can cross the blood-brain barrier that can induce β-amyloid plaque degradation • Currently phase clinical II trials

12. Summary Description of β-amyloid and origin: • A 4kDa peptide , extracellular cleavage product of the amyloid precursor protein (APP) • Two membrane-bound endoprotease cleave APP. β- and γ-secretase. β-amyloid in the brain is result of β-secretase cleavage. Normal function is not well understood and there is no loss of function in animals. β-amyloid plaques: • Sequence of plaque formation : oligomers -> fibrils -> β-sheets -> plaques. • Zinc and copper can contribute. Copper forms oxidative links between monomers. Links between monomers can create oxidative stress, oligomers, fibrillization and plaques. • They disrupt normal function of nerve fibers -> Alzheimer’s disease. Drug Strategies for reducing β-amyloid plaques and Drug Mechanism: • Decrease production of β-amyloid -> Use Semagacestat (γ-secretase inhibitor) OR use R-fluriprofen to upregulate other secretases that don’t produce β-amyloid. • Prevent/reduce aggregation of β-amyloid which may prevent the formation of amyloid plaque -> Can be done by Alzhemed through use of glycosaminoglycan mimetic OR PBT2 can chelate metal ions away from β-amyloid. • Increase the elimination of β-amyloid from the brain -> ACC-001 vaccine induces β-amyloid degradation through use of antibodies.

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