Novel amylin analogues reduce amyloid-β cross-seeding aggregation and neurotoxicity
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.
Document Type
Journal Article
Date of Publication
1-1-2022
Volume
87
Issue
1
PubMed ID
35275530
Publication Title
Journal of Alzheimer's disease : JAD
Publisher
IOS
School
School of Medical and Health Sciences / Centre of Excellence for Alzheimer's Disease Research and Care
RAS ID
52137
Copyright
subscription content
First Page
373
Last Page
390
Comments
Dharmaraj, G. L., Arigo, F. D., Young, K. A., Martins, R., Mancera, R. L., & Bharadwaj, P. (2022). Novel Amylin Analogues Reduce Amyloid-β Cross-Seeding Aggregation and Neurotoxicity. Journal of Alzheimer's Disease, 87(1), 1-18. https://doi.org/10.3233/JAD-215339