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Key Issues in pharmacotherapy of β -amyloid

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. What is β -amyloid?. A 4kDa peptide Cleavage product of the amyloid precursor protein (APP)

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Key Issues in pharmacotherapy of β -amyloid

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  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.

  13. Reference Murphy, M.P. (2010). Alzheimer’s Disease and the β-Amyloid Peptide. Journal of Alzheimer’s Disease, 19 (1): 1-17. Hiltunen, M., Groen, T.V., Jolkkonen, J. (2009). Functional Roles of Amyloid-β Protein Precursor and Amyloid-β Peptides: Evidence from Experimental Studies. Journal of Alzheimer’s Disease, 18: 401-412. Luo, Y., Bolon, B., Damore, M.A., Fitzpatrick, D., Liu, H., Zhang, J., Yan, Q., Vassar, R., Citron, M. (2003). BACE1 (β-secretase) knockout mice do not acquire compensatory gene expression changes or develop neural lesions over time. Neurology of Disease, 14: 81-88. Lemere C.A., Masliah E. (2010). Alzheimer disease be prevented by amyloid-beta immunotherapy? Nature Reviews Neurology, 6(2):108-19. Gervais, F., Paquette, J., Morissette, C., Krzywkowski, P., Yu, M., Azzi, M., . . . Tremblay, P. (2007). Targeting soluble A beta peptide with tramiprosate for the treatment of brain amyloidosis. Neurobiology of Aging, 28, 537-547. Alzheimer’s Association. (2008, June). Experimental Alzheimer Drugs Targeting Beta-Amyloid and the “Amyloid Hypothesis”. Alzheimer’s Association. Retrieved from http://www.alz.org/national/documents/topicsheet_betaamyloid.pdf Balducci C., Forloni G. (2011). APP transgenic mice: their use and limitations. Neuromolecular medicine, (13): 117-137. The New York Academy of Science. (2013). Targetting Metals in Alzheimer’s and Other Neurodegenerative Diseases. The New York Academy of Science. Retrieved from http://www.nyas.org/Publications/Ebriefings/Detail.aspx?cid=1fc1b1f4-1c78-46ba-85a1-0763632fa129

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