Simulations of cross-amyloid aggregation of amyloid-β and islet amyloid polypeptide fragments

Computational Investigation of Coaggregation and Cross-Seeding between Aβ and hIAPP Underpinning the Cross-Talk in Alzheimer’s Disease and Type 2 Diabetes

“…28,35,36 Moreover, recent computational simulations have shown that a mixture of Aβ 16−22 and hIAPP 20−29 fragments can readily form β-barrel oligomers, prompting inquiries about whether fulllength Aβ and hIAPP can also form similar β-barrel structures. 37 Previous computational studies on Aβ and hIAPP coaggregation primarily focused on either the structures and dynamics of full-length heterodimers 28,35 or the cooligomerization of multiple short fragments. 37,38 As we have shown previously, the structural dynamics of oligomers in amyloid aggregation is highly dependent on the oligomer size; 38−40 e.g., hIAPP 8−20 underwent α-helix to β-sheet transition only when the aggregates were at least hexamers.…”

“…Considering the coexistence of hIAPP and Aβ in the human brain and pancreas, ,− alongside the clinical overlaps between AD and T2D, , extensive studies have investigated the interplay between these peptides, encompassing coaggregation and cross-seeding phenomena. , hIAPP aggregates more rapidly than Aβ at equivalent concentrations, displaying significantly shorter lag phases in vitro . , Co-aggregation experiments reveal that a mixture of soluble Aβ and hIAPP exhibits a shorter aggregation lag phase than Aβ alone, albeit slightly longer than IAPP alone at the same total peptide concentrations . Fibrils formed by both Aβ and hIAPP can act as seeds, mutually promoting each other’s amyloid aggregation, though less efficiently than their self-seeding processes. , Computational simulations have extensively explored the molecular interactions underlying this cross-talk, including possible interactions between Aβ and hIAPP fibrils, ,− heterodimerization of Aβ and hIAPP, , and the coaggregation of amyloidogenic fragments from both peptides. , Notably, hotspot binding regions between Aβ and hIAPP have been identified in vitro and in silico , involving Aβ residues 11–21 and 30–42, and hIAPP residues 8–20 and 21–37. ,, Moreover, recent computational simulations have shown that a mixture of Aβ 16–22 and hIAPP 20–29 fragments can readily form β-barrel oligomers, prompting inquiries about whether full-length Aβ and hIAPP can also form similar β-barrel structures . Previous computational studies on Aβ and hIAPP coaggregation primarily focused on either the structures and dynamics of full-length heterodimers , or the co-oligomerization of multiple short fragments. , As we have shown previously, the structural dynamics of oligomers in amyloid aggregation is highly dependent on the oligomer size; − e.g., hIAPP 8–20 underwent α-helix to β-sheet transition only when the aggregates were at least hexamers .…”

“…Fibrils formed by both Aβ and hIAPP can act as seeds, mutually promoting each other’s amyloid aggregation, though less efficiently than their self-seeding processes. , Computational simulations have extensively explored the molecular interactions underlying this cross-talk, including possible interactions between Aβ and hIAPP fibrils, ,− heterodimerization of Aβ and hIAPP, , and the coaggregation of amyloidogenic fragments from both peptides. , Notably, hotspot binding regions between Aβ and hIAPP have been identified in vitro and in silico , involving Aβ residues 11–21 and 30–42, and hIAPP residues 8–20 and 21–37. ,, Moreover, recent computational simulations have shown that a mixture of Aβ 16–22 and hIAPP 20–29 fragments can readily form β-barrel oligomers, prompting inquiries about whether full-length Aβ and hIAPP can also form similar β-barrel structures . Previous computational studies on Aβ and hIAPP coaggregation primarily focused on either the structures and dynamics of full-length heterodimers , or the co-oligomerization of multiple short fragments. , As we have shown previously, the structural dynamics of oligomers in amyloid aggregation is highly dependent on the oligomer size; − e.g., hIAPP 8–20 underwent α-helix to β-sheet transition only when the aggregates were at least hexamers . Hence, further investigation of the coaggregation of multiple full-length Aβ and hIAPP molecules, as well as their cross-seeding interactions, is crucial for a more detailed understanding of their cross-talk underpinning the copathology of AD and T2D.…”

“…37 Previous computational studies on Aβ and hIAPP coaggregation primarily focused on either the structures and dynamics of full-length heterodimers 28,35 or the cooligomerization of multiple short fragments. 37,38 As we have shown previously, the structural dynamics of oligomers in amyloid aggregation is highly dependent on the oligomer size; 38−40 e.g., hIAPP 8−20 underwent α-helix to β-sheet transition only when the aggregates were at least hexamers. 40 Hence, further investigation of the coaggregation of multiple full-length Aβ and hIAPP molecules, as well as their crossseeding interactions, is crucial for a more detailed understanding of their cross-talk underpinning the copathology of AD and T2D.…”

Differential Epigenetic Status and Responses to Stressors between Retinal Cybrids Cells with African versus European Mitochondrial DNA: Insights into Disease Susceptibilities

“…Oxidative stress plays a significant role in the development and progress of diseases. For example, the accumulation of amyloid-β (Amyβ) is associated with Alzheimer’s disease (extracellular Aβ plaques), age-related macular degeneration (drusen), cardiomyopathy, and diabetes (islet amyloid aggregation) [ 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 ]. In all of these diseases, the accumulation of Amyβ is cytotoxic and contributes to the pathology.…”