Amylin–Aβ oligomers at atomic resolution using molecular dynamics simulations: a link between Type 2 diabetes and Alzheimer's disease

Abstract

Clinical studies identified Type 2 diabetes (T2D) as a risk factor of Alzheimer's disease (AD). One of the potential mechanisms that link T2D and AD is the loss of cells associated with degenerative changes. Amylin1-37 aggregates (the pathological species in T2D) were found to be co-localized with those of Aβ1-42 (the pathological species in AD) to form the Amylin1-37-Aβ1-42 plaques, promoting aggregation and thus contributing to the etiology of AD. However, the mechanisms by which Amylin1-37 co-aggregate with Aβ1-42 are still elusive. This work presents the interactions between Amylin1-37 oligomers and Aβ1-42 oligomers at atomic resolution applying extensive molecular dynamics simulations for relatively large ensemble of cross-seeding Amylin1-37 -Aβ1-42 oligomers. The main conclusions of this study are first, Aβ1-42 oligomers prefer to interact with Amylin1-37 oligomers to form single layer conformations (in-register interactions) rather than double layer conformations; and second, in some double layer conformations of the cross-seeding Amylin1-37 -Aβ1-42 oligomers, the Amylin1-37 oligomers destabilize the Aβ1-42 oligomers and thus inhibit Aβ1-42 aggregation, while in other double layer conformations, the Amylin1-37 oligomers stabilize Aβ1-42 oligomers and thus promote Aβ1-42 aggregation.

Melatonin ameliorates Aβ1-42-induced Alzheimer's cognitive deficits in mouse model

“…Previous evidences suggested that Aβ 1‐42 played a critical role in the pathogenesis of AD, but the underlying mechanisms remained unknown. A lot of studies have supported that melatonin prevents the death of injured neurons in the hippocampus and cortex and improves the cognitive function of brain .…”

Distinct oligomerization and fibrillization dynamics of amyloid core sequences of amyloid-beta and islet amyloid polypeptide

“…Emerging evidence suggests that interactions between different amyloid proteins and peptides may play a critical role in amyloid diseases (e.g., Aβ–tau 42 , tau-synuclein 43 , Aβ–transthyretin 44 , and IAPP–Aβ 45 ). For example, T2D has been identified as a major risk factor for AD 46–48 and thus the co-aggregation of IAPP and Aβ may contribute to the cross-talk between these two diseases 49,50 . Therefore, we also investigate in our simulations the co-aggregation between Aβ16–22 and IAPP22–28, experimentally identified as the hotspot regions for the inter-molecular interaction between full-length Aβ and IAPP 45 .…”

Coaggregation of κ‐Casein and β‐Lactoglobulin Produces Morphologically Distinct Amyloid Fibrils

“…Cross‐amyloid interactions and coaggregation of peptides into heteropolymeric amyloid fibrils occur in disease‐causing proteins including amylin and amyloid‐β, amylin and α‐synuclein, amyloid‐β and α‐synuclein, and the tau protein and amyloid‐β . The interactions and mechanisms of coaggregation between these proteins have been difficult to investigate due to a lack of atomic resolution structures, although molecular dynamics simulations are proving highly useful and have revealed how these proteins interact with each other as well as the synergistic effects of cross‐amyloid interactions in altering the secondary structures of coaggregated proteins.…”