TY - JOUR
T1 - Novel amylin analogues reduce amyloid-β cross-seeding aggregation and neurotoxicity
AU - Dharmaraj, Gowdame Lakshmanan
AU - Arigo, Fraulein Denise
AU - Young, Kimberly A.
AU - Martins, Ralph
AU - Mancera, Ricardo L.
AU - Bharadwaj, Prashant
PY - 2022
Y1 - 2022
N2 - 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.
AB - 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.
KW - Aggregation
KW - Alzheimer's disease
KW - amylin analogue
KW - amyloid-beta
KW - human islet amyloid polypeptide (hIAPP)
UR - http://www.scopus.com/inward/record.url?scp=85130002141&partnerID=8YFLogxK
U2 - 10.3233/JAD-215339
DO - 10.3233/JAD-215339
M3 - Article
C2 - 35275530
AN - SCOPUS:85130002141
SN - 1387-2877
VL - 87
SP - 373
EP - 390
JO - Journal of Alzheimer's Disease
JF - Journal of Alzheimer's Disease
IS - 1
ER -