Computational Investigation of Coaggregation and Cross-Seeding between Aß and hIAPP Underpinning the Cross-Talk in Alzheimer's Disease and Type 2 Diabetes.
J Chem Inf Model
; 64(13): 5303-5316, 2024 Jul 08.
Article
em En
| MEDLINE
| ID: mdl-38921060
ABSTRACT
The coexistence of amyloid-ß (Aß) and human islet amyloid polypeptide (hIAPP) in the brain and pancreas is associated with an increased risk of Alzheimer's disease (AD) and type 2 diabetes (T2D) due to their coaggregation and cross-seeding. Despite this, the molecular mechanisms underlying their interaction remain elusive. Here, we systematically investigated the cross-talk between Aß and hIAPP using atomistic discrete molecular dynamics (DMD) simulations. Our results revealed that the amyloidogenic core regions of both Aß (Aß10-21 and Aß30-41) and hIAPP (hIAPP8-20 and hIAPP22-29), driving their self-aggregation, also exhibited a strong tendency for cross-interaction. This propensity led to the formation of ß-sheet-rich heterocomplexes, including potentially toxic ß-barrel oligomers. The formation of Aß and hIAPP heteroaggregates did not impede the recruitment of additional peptides to grow into larger aggregates. Our cross-seeding simulations demonstrated that both Aß and hIAPP fibrils could mutually act as seeds, assisting each other's monomers in converting into ß-sheets at the exposed fibril elongation ends. The amyloidogenic core regions of Aß and hIAPP, in both oligomeric and fibrillar states, exhibited the ability to recruit isolated peptides, thereby extending the ß-sheet edges, with limited sensitivity to the amino acid sequence. These findings suggest that targeting these regions by capping them with amyloid-resistant peptide drugs may hold potential as a therapeutic approach for addressing AD, T2D, and their copathologies.
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Base de dados:
MEDLINE
Assunto principal:
Peptídeos beta-Amiloides
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Diabetes Mellitus Tipo 2
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Simulação de Dinâmica Molecular
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Polipeptídeo Amiloide das Ilhotas Pancreáticas
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Doença de Alzheimer
Limite:
Humans
Idioma:
En
Ano de publicação:
2024
Tipo de documento:
Article