A critical concentration of N-terminal pyroglutamylated amyloid beta drives the misfolding of Ab1-42 into more toxic aggregates

Galante, Denise; Ruggeri, Francesco Simone; Dietler, Giovanni; Pellistri, Francesca; Gatta, Elena; Corsaro, Alessandro; Florio, Tullio; Perico, Angelo; D’Arrigo, Cristina

doi:10.1016/j.biocel.2016.08.037

Cited by 43 publications

(50 citation statements)

References 46 publications

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“…This also indicates that cellular, genetic, or environmental cofactors may govern seeding formation and its acceleration in pathological conditions (75). Interestingly, this increased capability to induce full-length A␤ seeding has been described for several truncated A␤ variants such as A␤24 (43) and pE3A␤ (76).…”

Section: Biophysical Properties Of Truncated Peptidesmentioning

confidence: 88%

“…Glutamate cyclization results in the loss of a negative charge that contributes to the hydrophobicity, resistance to catabolism (77), and aggregation propensity of N-terminally truncated A␤ species pE11-A␤ and pE3-A␤. pE3-42A␤ influences misfolding of full-length unmodified A␤ (76). Moreover, pEA␤ peptides are known to seed the aggregation of other A␤ fragments.…”

Section: Biophysical Properties Of Truncated Peptidesmentioning

confidence: 99%

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Are N- and C-terminally truncated Aβ species key pathological triggers in Alzheimer's disease?

Dunys

Valverde

Checler

2018

Journal of Biological Chemistry

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The histopathology of Alzheimer's disease (AD) is characterized by neuronal loss, neurofibrillary tangles, and senile plaque formation. The latter results from an exacerbated production (familial AD cases) or altered degradation (sporadic cases) of 40/42-amino acid-long β-amyloid peptides (Aβ peptides) that are produced by sequential cleavages of Aβ precursor protein (βAPP) by β- and γ-secretases. The amyloid cascade hypothesis proposes a key role for the full-length Aβ42 and the Aβ40/42 ratio in AD etiology, in which soluble Aβ oligomers lead to neurotoxicity, tau hyperphosphorylation, aggregation, and, ultimately, cognitive defects. However, following this postulate, during the last decade, several clinical approaches aimed at decreasing full-length Aβ42 production or neutralizing it by immunotherapy have failed to reduce or even stabilize AD-related decline. Thus, the Aβ peptide (Aβ40/42)-centric hypothesis is probably a simplified view of a much more complex situation involving a multiplicity of APP fragments and Aβ catabolites. Indeed, biochemical analyses of AD brain deposits and fluids have unraveled an Aβ peptidome consisting of additional Aβ-related species. Such Aβ catabolites could be due to either primary enzymatic cleavages of βAPP or secondary processing of Aβ itself by exopeptidases. Here, we review the diversity of N- and C-terminally truncated Aβ peptides and their biosynthesis and outline their potential function/toxicity. We also highlight their potential as new pharmaceutical targets and biomarkers.

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Section: Biophysical Properties Of Truncated Peptidesmentioning

confidence: 88%

Section: Biophysical Properties Of Truncated Peptidesmentioning

confidence: 99%

Are N- and C-terminally truncated Aβ species key pathological triggers in Alzheimer's disease?

Dunys

Valverde

Checler

2018

Journal of Biological Chemistry

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“…[17] Moreover, AbpE3-42 showed a faster aggregation kinetics than the full length and at the same time inhibited Ab1-42 fibrillogenesis. [18][19][20] Notably, small quantities of AbpE3-42 have been observed to enhance the neurotoxicity of Ab1-42, [6,21] by a "prion-like" behavior.…”

Section: Introductionmentioning

confidence: 99%

“…[22,23] Conflicting results concerning oxidative properties of Ab have been reported. [23] As a matter of fact, it was reported that Ab is able to reduce Cu 21 and Fe 31 [24,25] however, other studies have shown the inability of Ab, in the absence of a cofactor (ie, a reductant), to reduce Cu 21 . [26] Ab-Cu and Ab-Fe complexes are able to catalyze the production of H 2 O 2 not only in the presence of a reducing agent [27] such as ascorbate, l-dopa, and dopamine, but also with cholesterol, progesterone, and NADPH.…”

Section: Introductionmentioning

confidence: 99%

Effect of ferric citrate on amyloid‐beta peptides behavior

et al. 2018

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Amyloid beta (Aβ) aggregation and oxidative stress are two of the central events in Alzheimer's Disease (AD). Both these phenomena can be caused by the interaction of Aβ with metal ions. In the last years the interaction between Zn , Cu , and Aβ was much studied, but between iron and Aβ it is still little known. In this work we determine how three Aβ peptides, present in AD, interact with Fe -citrate. The three Aβ peptides are: full length Aβ1-42, an isoform truncated at Glutamic acid in position three, Aβ3-42, and its pyroglutamated form AβpE3-42. Conformation and morphology of the three peptides, aggregated with and without Fe -citrate were studied. Besides, we have determined the strength of the interactions Aβ/Fe -citrate studying the effect of ethylenediaminetetraacetic acid as chelator. Results reported here demonstrate that Fe -citrate promotes the aggregation in all the three peptides. Moreover, Aspartic acid 1, Glutamic acid 3, and Tyrosine 10 have an important role in the coordination with iron, generating a more stable complex for Aβ1-42 compared to that for the truncated peptides.

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“…1c). [24][25][26][27][28][29][30][31][32][33][34] AFM-IR is becoming widely applicable in biology since is capable of acquiring simultaneously morphological, nanomechanical and nanoscale-resolved chemical IR maps and absorption spectra from protein aggregates, liquid-liquid phase separated condensates, chromosomes, and single cells. 29,31,[34][35][36] As fundamental achievement, we have recently demonstrated that AFM-IR enables to acquire infrared absorption spectra for secondary structure determination from single protein molecules.…”

mentioning

confidence: 99%

Infrared Nanospectroscopy Reveals the Molecular Interaction Fingerprint of an Aggregation Inhibitor with Single Aβ42 Oligomers

Ruggeri

Habchi

Chia

et al. 2020

Preprint

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Very significant efforts have been devoted in the last twenty years to developing compounds that can interfere with the aggregation pathways of proteins related to misfolding disorders, including Alzheimer's and Parkinson's diseases. However, no disease-modifying drug has become available for clinical use to date for these conditions. One of the main reasons for this failure is the incomplete knowledge of the molecular mechanisms underlying the process by which small molecules interact with protein aggregates and interfere with their aggregation pathways. Here, we leverage the single molecule level morphological and chemical sensitivity of infrared nanospectroscopy to provide the first direct measurement of the interaction between single A42 oligomeric and fibrillar species and an aggregation inhibitor, bexarotene, originally an anticancer drug capable recently shown to be able to inhibit A42 aggregation in animal models of Alzheimer's disease.Our results demonstrate that the carbonyl group of this compound interacts with A42 aggregates through a single hydrogen bond. These results establish infrared nanospectroscopy as powerful tool in structure-based drug discovery for protein misfolding diseases.Alzheimer's disease (AD) is characterised by memory loss and cognitive impairment. AD is the primary cause of dementia, which affects currently over 50 million people worldwide, a number expected to exceed 150 million by 2050. 1-3 The self-assembly of the 42-residue isoform of the amyloid- (A) peptide into intractable aggregates is considered to be at the core of the molecular pathways leading to AD. [3][4][5] It is therefore important to understand at the molecular level the aggregation process of A42 in order to develop effective therapeutic strategies that aim at inhibiting its self-assembly.Great efforts have been devoted in the last twenty years to understand the molecular basis of this devastating disorder and to develop small molecules that could interfere with the aggregation pathway of A42. 6-12 Indeed, disease-modifying small molecules represent c.a. one third of the registered trials, in which anti-A therapies dominate. 13 However, despite these efforts, no compound has entered the clinical use to date. 13,14 These repeated failures are in part related to an incomplete understanding of the molecular mechanisms underlying the process by which small molecules interact with protein aggregates and how they interfere with the pathways of aggregation. It is increasingly recognised that inhibiting A aggregation per se could have unexpected consequences on the toxicity, as it could not only decrease it, but also leave it unaffected, or even increase it. 15 This complexity is due to the non-linear nature of the aggregation network, in which neurotoxic small oligomeric intermediates [16][17][18][19][20] , can be formed in a variety of ways, some of which highly sensitive to small perturbation. Therefore, promising effective therapeutic strategies must be aimed at targeting precise species in a controlled inte...

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A critical concentration of N-terminal pyroglutamylated amyloid beta drives the misfolding of Ab1-42 into more toxic aggregates

Cited by 43 publications

References 46 publications

Are N- and C-terminally truncated Aβ species key pathological triggers in Alzheimer's disease?

Are N- and C-terminally truncated Aβ species key pathological triggers in Alzheimer's disease?

Effect of ferric citrate on amyloid‐beta peptides behavior

Infrared Nanospectroscopy Reveals the Molecular Interaction Fingerprint of an Aggregation Inhibitor with Single Aβ42 Oligomers

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