Poster Presentation 7th Modern Solid Phase Peptide Synthesis & Its Applications Symposium 2019

The effects of site-specific modification of Aβ-AGEs and Aβ-ALEs in Alzheimer’s Disease (#115)

Iman Kavianinia 1 2 , Harveen Kaur 2 , Jin Ng 3 , Johanes K Kasim 3 , Jakob Gaar 2 , Jane Allison 3 , Paul Harris 1 3 , Nigel Birch 3 , Margaret Brimble 1 2
  1. Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, 3A Symonds Street, Auckland 1010, New Zealand
  2. School of Chemical Sciences, The University of Auckland, 23 Symonds Street, Auckland 1010, New Zealand
  3. School of Biological Sciences, 3A Symonds Street, The University of Auckland, Auckland, New Zealand

An estimated 50 million people worldwide are living with Alzheimer's Disease (AD) or other related neurodegenerative diseases.1 Aβ plaques are one of the primary brain pathologies of AD. However, there is increasing evidence that Aβ plaques modified either by sugar derivatives [known as advanced glycation endproducts (AGEs)], or by reactive aldehyde moieties generated from lipid peroxidation [known as advanced lipoxidation end products (ALEs)], are more pathogenic than the Aβ plaques themselves.2

Previous studies monitoring the effects of AGEs and ALEs on Aβ plaques used incubation techniques which resulted in a complex mixture of Aβ-AGE and Aβ-ALE peptides. To address this issue, site-specifically modified Aβ peptides synthesized using solid phase peptide synthesis (SPPS) would allow for better understanding of how AGEs and ALEs individually affect the pathogenesis of AD.

Recently, we developed a technique to incorporate AGEs3 and ALEs4 at precise locations on a peptide, which enabled us to evaluate the effects of site-specific modifications on the Aβ peptide. Furthermore, we have reported the successful synthesis of the Aβ(1-42) peptide using a temporary C-terminal tag enabling the preparation of synthetic Aβ(1-42) in high yield and purity.5 These results will be discussed, along with the effects of site-specific glycations on Aβ(1-42) in terms of peptide behaviour and the effect on neuronal mitochondrial function.6 We Found that Aβ-AGE16 and Aβ-AGE28 were neurotoxic, possibly through a nonmitochondrial pathway, whereas Aβ-AGE16&28 showed no neurotoxicity. Therefore, our results provides insight into potential therapeutic approaches against neurotoxic glycated Aβ(1-42).

  1. 1. Alzheimer’s Disease International, World Alzheimer Report, 2018: The State of the Art of Dementia Research: New Frontiers, Alzheimer’s Disease International (ADI), London, 2018.
  2. 2. Sasaki, N.; Fukatsu, R.; Tsuzuki, K.; Hayashi, Y.; Yoshida, T.; Fujii, N.; Koike, T.; Wakayama, I.; Yanagihara, R.; Garruto, R., Advanced glycation end products in Alzheimer's disease and other neurodegenerative diseases. The American Journal of Pathology 1998, 153 (4), 1149-11554. Sultana, R.; Perluigi, M.; Butterfield, D. A., Lipid peroxidation triggers neurodegeneration: a redox proteomics view into the Alzheimer disease brain. Free Radical Biology and Medicine 2013, 62, 157-169.
  3. 3. Kaur, H.; Kamalov, M.; Brimble, M. A. Chemical Synthesis of Peptides Containing Site-Specific Advanced Glycation Endproducts. Accounts of Chemical Research. 2016, 49 (10), 2199-2208.
  4. 4. Kavianinia, I.; Yang, SH.; Kaur, H.; Harris, P. W.; Renwick C. J.; Fairbanks, A. J.; Brimble, M. A., Synthesis and incorporation of an advanced lipid peroxidation end-product building block into collagen mimetic peptides. Chemical Communications 2017, 53 (60), 8459-8462.
  5. 5. Kasim, J. K.; Kavianinia, I.; Ng, J.; Harris, P. W.; Birch, N. P.; Brimble, M. A., Efficient synthesis and characterisation of the amyloid beta peptide, Aβ 1–42, using a double linker system. Organic & Biomolecular Chemistry 2019, 17 (1), 30-34.
  6. 6. Ng, J.; Kaur, H.; Collier, T.; Chang, K.; Brooks, A. E.; Allison, J. R.; Brimble, M. A.; Hickey, A.; Birch, N. P. Journal of Biological Chemistry 2019, 294, 8806–8818