Dataset Information

Amyloid-? 1-24 C-terminal truncated fragment promotes amyloid-? 1-42 aggregate formation in the healthy brain.

ABSTRACT: Substantial data indicate that amyloid-? (A?), the major component of senile plaques, plays a central role in Alzheimer's Disease and indeed the assembly of naturally occurring amyloid peptides into cytotoxic aggregates is linked to the disease pathogenesis. Although A?42 is a highly aggregating form of A?, the co-occurrence of shorter A? peptides might affect the aggregation potential of the A? pool. In this study we aimed to assess whether the structural behavior of human A?42 peptide inside the brain is influenced by the concomitant presence of N-terminal fragments produced by the proteolytic activity of glial cells. We show that the occurrence of the human C-terminal truncated 1-24 A? fragment impairs A?42 clearance through blood brain barrier and promotes the formation of A?42 aggregates even in the healthy brain. By showing that A?1-24 has seeding properties for aggregate formation in intracranially injected wild type mice, our study provide the proof-of-concept that peptides produced upon A?42 cleavage by activated glial cells may cause phenotypic defects even in the absence of genetic mutations associated with Alzheimer's Disease, possibly contributing to the development of the sporadic form of the pathology.

SUBMITTER: Mazzitelli S

PROVIDER: S-EPMC5057504 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

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Publications

Amyloid-β 1-24 C-terminal truncated fragment promotes amyloid-β 1-42 aggregate formation in the healthy brain.

Mazzitelli Sonia S Filipello Fabia F Rasile Marco M Lauranzano Eliana E Starvaggi-Cucuzza Chiara C Tamborini Matteo M Pozzi Davide D Barajon Isabella I Giorgino Toni T Natalello Antonino A Matteoli Michela M

Acta neuropathologica communications 20161010 1

Substantial data indicate that amyloid-β (Aβ), the major component of senile plaques, plays a central role in Alzheimer's Disease and indeed the assembly of naturally occurring amyloid peptides into cytotoxic aggregates is linked to the disease pathogenesis. Although Aβ42 is a highly aggregating form of Aβ, the co-occurrence of shorter Aβ peptides might affect the aggregation potential of the Aβ pool. In this study we aimed to assess whether the structural behavior of human Aβ42 peptide inside t ...[more]

PMID: 27724899

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Project description:As an important neuropathological hallmark of Alzheimer's disease (AD), the oligomerization of amyloid-β (Aβ) peptides has been intensively investigated in both theoretical and experimental studies. However, the oligomerization space in terms of the kinetics, molecular mechanism, and oligomer structures remains mysterious to us. An equation that can quantitatively describe the time it takes for Aβ oligomers to appear in the human brain at a given Aβ monomer concentration is extremely vital for us to understand the development and disease progression of AD. In this study, we utilized molecular dynamics (MD) simulations to investigate the oligomerization of Aβ42 peptides at five different monomer concentrations. We have elucidated the formation pathways of Aβ tetramers, characterized the oligomer structures, estimated the oligomerization time for Aβ dimers, trimers, and tetramers, and for the first-time derived equations that could quantitatively describe the relationship between the oligomerization time and the monomer concentration. Applying these equations, our prediction of oligomerization time agrees well with the experimental and clinical findings, in spite of the limitations of our oligomerization simulations. We have found that the Aβ oligomerization time depends on the monomer concentration by a power of -2.4. The newly established equations will enable us to quantitatively estimate the risk score of AD, which is a function of age. Moreover, we have identified the most dominant pathway of forming Aβ tetramers, probably the most important and toxic Aβ oligomer. Our results have shown that the structures of Aβ42 dimer, trimer, and tetramer, which are distinguishable from each other, depend on the monomer concentration at which the oligomers form. Representative oligomer structures, which can serve as potential drug targets, have been identified by clustering analysis. The MD sampling adequacy has been validated by the excellent agreement between the calculated and measured collisional cross section (CCS) parameters (the prediction errors are within 2%). In a conclusion, this study provides the kinetics and structure basis for developing inhibitors to decelerate the Aβ oligomerization process.

Dataset Information

Amyloid-? 1-24 C-terminal truncated fragment promotes amyloid-? 1-42 aggregate formation in the healthy brain.

Publications

Amyloid-β 1-24 C-terminal truncated fragment promotes amyloid-β 1-42 aggregate formation in the healthy brain.

Similar Datasets

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