Novel amylin analogues reduce amyloid-β cross-seeding aggregation and neurotoxicity

Gowdame Lakshmanan Dharmaraj, Fraulein Denise Arigo, Kimberly A. Young, Ralph Martins, Ricardo L. Mancera, Prashant Bharadwaj*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

4 Citations (Scopus)

Abstract

Background: Type 2 diabetes related human islet amyloid polypeptide (hIAPP) plays a dual role in Alzheimer's disease (AD). hIAPP has neuroprotective effects in AD mouse models whereas, high hIAPP concentrations can promote co-Aggregation with amyloid-β (Aβ) to promote neurodegeneration. In fact, both low and high plasma hIAPP concentration has been associated with AD. Therefore, non-Aggregating hIAPP analogues have garnered interest as a treatment for AD. The aromatic amino acids F23 and I26 in hIAPP have been identified as the key residues involved in self-Aggregation and Aβ cross-seeding. Objective: Three novel IAPP analogues with single and double alanine mutations (A1 = F23, A2 = I26, and A3 = F23 + I26) were assessed for their ability to aggregate, modulate Aβ oligomer formation, and alter neurotoxicity. Methods: A range of biophysical methods including Thioflavin-T, gel electrophoresis, photo-crosslinking, circular dichroism combined with cell viability assays were utilized to assess protein aggregation and toxicity. Results: All IAPP analogues showed significantly less self-Aggregation than hIAPP. Co-Aggregated Aβ42-A2 and A3 also showed reduced aggregation compared to Aβ42-hIAPP mixtures. Self-and co-oligomerized A1, A2, and A3 exhibited random coil conformations with reduced beta sheet content compared to hIAPP and Aβ42-hIAPP aggregates. A1 was toxic at high concentrations compared to A2 and A3. However, co-Aggregated Aβ42-A1, A2, or A3 showed reduced neurotoxicity compared to Aβ42, hIAPP, and Aβ42-hIAPP aggregates. Conclusion: These findings confirm that hIAPP analogues with non-Aromatic residues at positions 23 and 26 have reduced self-Aggregation and the ability to neutralize Aβ42 toxicity. This warrants further characterization of their protective effects in pre-clinical AD models.

Original languageEnglish
Pages (from-to)373-390
Number of pages18
JournalJournal of Alzheimer's Disease
Volume87
Issue number1
DOIs
Publication statusPublished - 2022

Keywords

  • Aggregation
  • Alzheimer's disease
  • amylin analogue
  • amyloid-beta
  • human islet amyloid polypeptide (hIAPP)

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