Amyloid β Modification: A Key to the Sporadic Alzheimer's Disease?

Barykin, Evgeny P.; Mitkevich, Vladimir A.; Kozin, Sergey A.; Makarov, Alexander А.

doi:10.3389/fgene.2017.00058

Cited by 58 publications

(64 citation statements)

References 54 publications

(53 reference statements)

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“…Amyloid-b peptide (Ab) aggregation remains to be viewed as one of the causative factors in Alzheimer's disease (AD) as a part of the amyloid hypothesis (1)(2)(3)(4). It is believed that Ab accumulation is a trigger that initiates a pathological cascade implicating t protein, synuclein, and other aggregation-prone proteins (2,3). The structural polymorphism of amyloid fibrils is a challenging and potentially pathologically important factor in the molecular basis of AD (5)(6)(7)(8)(9).…”

Section: Introductionmentioning

confidence: 99%

“…This polymorphism occurs at multiple levels (10), leading to many possible fibrillar structures from the same Ab protein as well as the existence of multiple molecular variants of Ab, including 1-39, 1-40, and 1-42, and the variants of these with post-translational modifications (PTMs) and mutations. The majority of PTMs occur in the flexible N-terminal region of the fibrils, encompassing residues 1-16, and are thought to trigger or accelerate the fibrillation of wild-type Ab peptides (2,11,12). However, the pathological roles of modified Ab in AD have not been determined in detail.…”

Section: Introductionmentioning

confidence: 99%

“…However, the pathological roles of modified Ab in AD have not been determined in detail. It has been suggested that PTMs may be responsible for sporadic cases of AD, which encompass 90% of all patients (2,11). On the contrary, many familial-type mutations that cause the early onset of the disease occur around the b-bend region of Ab, comprising residues 21-23, and are associated with altered folds, higher aggregation propensities, and higher toxicities (13)(14)(15)(16).…”

Section: Introductionmentioning

confidence: 99%

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Effect of Post-Translational Modifications and Mutations on Amyloid-β Fibrils Dynamics at N Terminus

Vugmeyster

Ostrovsky

et al. 2019

Biophysical Journal

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We investigate the variability in the dynamics of the disordered N-terminal domain of amyloid-b fibrils (Ab), comprising residues 1-16 of Ab 1-40 , due to post-translational modifications and mutations in the b-bend regions known to modulate aggregation properties. Using 2 H static solid-state NMR approaches, we compare the dynamics in the wild-type Ab fibrils in the threefold symmetric polymorph with the fibrils from three post-translational modification sequences: isoaspartate-D7, the phosphorylation of S8, and an N-terminal truncation DE3. Additional comparisons are made with the mutants in the b-bend region (residues 21-23) corresponding to the familial Osaka E22D deletion and D23N Iowa mutation. We also include the aggregates induced by Zn 2þ ions. The dynamics are probed at the F4 and G9 positions. The main motional model involves two free states undergoing diffusion and conformational exchanges with the bound state in which the diffusion is quenched because of transient interactions involving fibril core and other intrastrand contacts. The fraction of the bound state increases in a sigmoidal fashion with a decrease in temperature. There is clear variability in the dynamics: the phosphorylation of S8 variant is the most rigid at the G9 site in line with structural studies, the DE3 fibrils are more flexible at the G9 site in line with the morphological fragmentation pattern, the Zn-induced aggregates are the most mobile, and the two b-bend mutants have the strongest changes at the F4 site toward higher rigidity. Overall, the changes underlie the potential role of conformational ensembles in setting the stage for aggregation-prone states.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Effect of Post-Translational Modifications and Mutations on Amyloid-β Fibrils Dynamics at N Terminus

Vugmeyster

Ostrovsky

et al. 2019

Biophysical Journal

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“…In vitro studies have also demonstrated that certain PTM-Aβs grew fibrils more rapidly than their wt-Aβ analogs and possessed higher levels of neuronal cytotoxicity (9,18,19). Certain PTM-Aβ subtypes were thought to trigger or accelerate the fibrillation of wt-Aβ peptides (20,21). However, the structural basis of the pathological roles of PTM-Aβs has not been determined.…”

mentioning

confidence: 99%

Molecular structure of an N-terminal phosphorylated β-amyloid fibril

Vugmeyster

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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The structural polymorphism in β-amyloid (Aβ) plaques from Alzheimer disease (AD) has been recognized as an important pathological factor. Plaques from sporadic AD patients contain fibrillar deposits of various amyloid proteins/peptides, including posttranslational modified Aβ (PTM-Aβ) subtypes. Although many PTM-Aβs were shown to accelerate the fibrillation process, increase neuronal cytotoxicity of aggregates, or enhance the stability of fibrils, the contribution of PTM-Aβs to structural polymorphisms and their pathological roles remains unclear. We report here the NMR-based structure for the Ser-8-phosphorylated 40-residue Aβ (pS8-Aβ40) fibrils, which shows significant difference to the wild-type fibrils, with higher cross-seeding efficiency and thermodynamic stability. Given these physicochemical properties, the structures originated from pS8-Aβ40 fibrils may potentially dominate the polymorphisms in the mixture of wild-type and phosphorylated Aβ deposits. Our results imply that Aβ subtypes with “seeding-prone” properties may influence the polymorphisms of amyloid plaques through the cross-seeding process.

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“…One of the most common component of amyloid plaques is the Aβ isoform with an isomerized aspartic acid residue at position 7 (isoAβ) 8 , 11 . We hypothesized that this Aβ isoform is a major player in AD pathogenesis 12 , 13 . We have shown that, in contrast to intact Aβ42, a synthetic peptide corresponding to isoAβ42 causes cerebral amyloidogenesis in AD animal models 14 , 15 .…”

Section: Introductionmentioning

confidence: 99%

Amyloid-β with isomerized Asp7 cytotoxicity is coupled to protein phosphorylation

Zatsepina

Kechko

Mitkevich

et al. 2018

Sci Rep

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Neuronal dysfunction and loss associated with the accumulation of amyloid-β (Aβ) in the form of extracellular amyloid plaques and hyperphosphorylated tau in the form of intraneuronal neurofibrillary tangles represent key features of Alzheimer’s disease (AD). Amyloid plaques found in the brains of AD patients are predominantly composed of Aβ42 and its multiple chemically or structurally modified isoforms. Recently, we demonstrated that Aβ42 with isomerised Asp7 (isoAβ42) which is one of the most abundant Aβ isoform in plaques, exhibited high neurotoxicity in human neuronal cells. Here, we show that, in SH-SY5Y neuroblastoma cells, the administration of synthetic isoAβ42 rather than intact Aβ42 resulted in a significantly higher level of protein phosphorylation, especially the phosphorylation of tau, tubulins, and matrin 3. IsoAβ42 induced a drastic reduction of tau protein levels. Our data demonstrate, for the first time, that isoAβ42, being to date the only known synthetic Aβ species to cause AD-like amyloidogenesis in an animal AD model, induced cell death by disabling structural proteins in a manner characteristic of that observed in the neurons of AD patients. The data emphasize an important role of isoAβ42 in AD progression and provide possible neurotoxicity paths for this particular isoform.

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Amyloid β Modification: A Key to the Sporadic Alzheimer's Disease?

Cited by 58 publications

References 54 publications

Effect of Post-Translational Modifications and Mutations on Amyloid-β Fibrils Dynamics at N Terminus

Effect of Post-Translational Modifications and Mutations on Amyloid-β Fibrils Dynamics at N Terminus

Molecular structure of an N-terminal phosphorylated β-amyloid fibril

Amyloid-β with isomerized Asp7 cytotoxicity is coupled to protein phosphorylation

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