Dataset Information

Few Ramachandran Angle Changes Provide Interaction Strength Increase in A?42 versus A?40 Amyloid Fibrils.

ABSTRACT: The pathology of Alzheimer's disease can ultimately be traced to the increased aggregation stability of A?42 peptides which possess two extra residues (Ile 41 &Ala 42) that the non-pathological strain (A?40) lacks. We have found A?42 fibrils to exhibit stronger energies in inter-chain interactions and we have also identified the cause for this increase to be the result of different Ramachandran angle values in certain residues of the A?42 strain compared to A?40. These unique angle configurations result in the peptide planes in the fibril structures to be more vertical along the fibril axis for A?42 which thus reduces the inter-atomic distance between interacting atoms on vicinal peptide chains thereby increasing the electrostatic interaction energies. We lastly postulate that these different Ramachandran angle values could possibly be traced to the unique conformational folding avenues sampled by the A?42 peptide owing to the presence of its two extra residues.

SUBMITTER: Bastidas OH

PROVIDER: S-EPMC5093553 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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Few Ramachandran Angle Changes Provide Interaction Strength Increase in Aβ42 versus Aβ40 Amyloid Fibrils.

Bastidas Oscar H OH Green Benjamin B Sprague Mary M Peters Michael H MH

Scientific reports 20161103

The pathology of Alzheimer's disease can ultimately be traced to the increased aggregation stability of Aβ42 peptides which possess two extra residues (Ile 41 &Ala 42) that the non-pathological strain (Aβ40) lacks. We have found Aβ42 fibrils to exhibit stronger energies in inter-chain interactions and we have also identified the cause for this increase to be the result of different Ramachandran angle values in certain residues of the Aβ42 strain compared to Aβ40. These unique angle configuration ...[more]

PMID: 27808259

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Project description:BackgroundCathepsin D (CatD) is a lysosomal protease that degrades both the amyloid β-protein (Aβ) and the microtubule-associated protein, tau, and has been genetically linked to late-onset Alzheimer disease (AD). Here, we sought to examine the consequences of genetic deletion of CatD on Aβ proteostasis in vivo and to more completely characterize the degradation of Aβ42 and Aβ40 by CatD.MethodsWe quantified Aβ degradation rates and levels of endogenous Aβ42 and Aβ40 in the brains of CatD-null (CatD-KO), heterozygous null (CatD-HET), and wild-type (WT) control mice. CatD-KO mice die by ~ 4 weeks of age, so tissues from younger mice, as well as embryonic neuronal cultures, were investigated. Enzymological assays and surface plasmon resonance were employed to quantify the kinetic parameters (KM, kcat) of CatD-mediated degradation of monomeric human Aβ42 vs. Aβ40, and the degradation of aggregated Aβ42 species was also characterized. Competitive inhibition assays were used to interrogate the relative inhibition of full-length human and mouse Aβ42 and Aβ40, as well as corresponding p3 fragments.ResultsGenetic deletion of CatD resulted in 3- to 4-fold increases in insoluble, endogenous cerebral Aβ42 and Aβ40, exceeding the increases produced by deletion of an insulin-degrading enzyme, neprilysin or both, together with readily detectable intralysosomal deposits of endogenous Aβ42-all by 3 weeks of age. Quite significantly, CatD-KO mice exhibited ~ 30% increases in Aβ42/40 ratios, comparable to those induced by presenilin mutations. Mechanistically, the perturbed Aβ42/40 ratios were attributable to pronounced differences in the kinetics of degradation of Aβ42 vis-à-vis Aβ40. Specifically, Aβ42 shows a low-nanomolar affinity for CatD, along with an exceptionally slow turnover rate that, together, renders Aβ42 a highly potent competitive inhibitor of CatD. Notably, the marked differences in the processing of Aβ42 vs. Aβ40 also extend to p3 fragments ending at positions 42 vs. 40.ConclusionsOur findings identify CatD as the principal intracellular Aβ-degrading protease identified to date, one that regulates Aβ42/40 ratios via differential degradation of Aβ42 vs. Aβ40. The finding that Aβ42 is a potent competitive inhibitor of CatD suggests a possible mechanistic link between elevations in Aβ42 and downstream pathological sequelae in AD.

Dataset Information

Few Ramachandran Angle Changes Provide Interaction Strength Increase in A?42 versus A?40 Amyloid Fibrils.

Publications

Few Ramachandran Angle Changes Provide Interaction Strength Increase in Aβ42 versus Aβ40 Amyloid Fibrils.

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