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Ion channel formation by N-terminally truncated Aβ (4-42): relevance for the pathogenesis of Alzheimer's disease.

ABSTRACT: Aβ deposition is a pathological hallmark of Alzheimer's disease (AD). Besides the full-length amyloid forming peptides (Aβ_1-40 and Aβ_1-42), biochemical analyses of brain deposits have identified a variety of N- and C-terminally truncated Aβ variants in sporadic and familial AD patients. However, their relevance for AD pathogenesis remains largely understudied. We demonstrate that Aβ_4-42 exhibits a high tendency to form β-sheet structures leading to fast self-aggregation and formation of oligomeric assemblies. Atomic force microscopy and electrophysiological studies reveal that Aβ_4-42 forms highly stable ion channels in lipid membranes. These channels that are blocked by monoclonal antibodies specifically recognizing the N-terminus of Aβ_4-42. An Aβ variant with a double truncation at phenylalanine-4 and leucine 34, (Aβ_4-34), exhibits unstable channel formation capability. Taken together the results presented herein highlight the potential benefit of C-terminal proteolytic cleavage and further support an important pathogenic role for N-truncated Aβ species in AD pathophysiology.

SUBMITTER: Karkisaval AG

PROVIDER: S-EPMC8132454 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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Ion channel formation by N-terminally truncated Aβ (4-42): relevance for the pathogenesis of Alzheimer's disease.

Karkisaval Abhijith G AG Rostagno Agueda A Azimov Rustam R Ban Deependra K DK Ghiso Jorge J Kagan Bruce L BL Lal Ratnesh R

Nanomedicine : nanotechnology, biology, and medicine 20200610

Aβ deposition is a pathological hallmark of Alzheimer's disease (AD). Besides the full-length amyloid forming peptides (Aβ1-40 and Aβ1-42), biochemical analyses of brain deposits have identified a variety of N- and C-terminally truncated Aβ variants in sporadic and familial AD patients. However, their relevance for AD pathogenesis remains largely understudied. We demonstrate that Aβ4-42 exhibits a high tendency to form β-sheet structures leading to fast self-aggr ...[more]

PMID: 32531337

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Project description:Calcium ion regulation plays a crucial role in maintaining neuronal functions such as neurotransmitter release and synaptic plasticity. Copper (Cu2+ ) coordination to amyloid-β (Aβ) has accelerated Aβ1-42 aggregation that can trigger calcium dysregulation by enhancing the influx of calcium ions by extensive perturbing integrity of the membranes. Aβ1-42 aggregation, calcium dysregulation, and membrane damage are Alzheimer disease (AD) implications. To gain a detail of calcium ions' role in the full-length Aβ1-42 and Aβ1-42 -Cu2+ monomers contact, the cellular membrane before their aggregation to elucidate the neurotoxicity mechanism, we carried out 2.5 μs extensive molecular dynamics simulation (MD) to rigorous explorations of the intriguing feature of the Aβ1-42 and Aβ1-42 -Cu2+ interaction with the dimyristoylphosphatidylcholine (DMPC) bilayer in the presence of calcium ions. The outcome of the results compared to the same simulations without calcium ions. We surprisingly noted robust binding energies between the Aβ1-42 and membrane observed in simulations containing without calcium ions and is two and a half fold lesser in the simulation with calcium ions. Therefore, in the case of the absence of calcium ions, N-terminal residues of Aβ1-42 deeply penetrate from the surface to the center of the bilayer; in contrast to calcium ions presence, the N- and C-terminal residues are involved only in surface contacts through binding phosphate moieties. On the other hand, Aβ1-42 -Cu2+ actively participated in surface bilayer contacts in the absence of calcium ions. These contacts are prevented by forming a calcium bridge between Aβ1-42 -Cu2+ and the DMPC bilayer in the case of calcium ions presence. In a nutshell, Calcium ions do not allow Aβ1-42 penetration into the membranes nor contact of Aβ1-42 -Cu2+ with the membranes. These pieces of information imply that the calcium ions mediate the membrane perturbation via the monomer interactions but do not damage the membrane; they agree with the western blot experimental results of a higher concentration of calcium ions inhibit the membrane pore formation by Aβ peptides.

Dataset Information

Ion channel formation by N-terminally truncated Aβ (4-42): relevance for the pathogenesis of Alzheimer's disease.

Publications

Ion channel formation by N-terminally truncated Aβ (4-42): relevance for the pathogenesis of Alzheimer's disease.

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