The Effects of N-terminal Mutations on β-amyloid Peptide Aggregation and Toxicity

Foroutanpay, Bahram V; Kumar, Jitendra; Kang, Sang Gyun; Danaei, N.; Westaway, David; Sim, Valerie L.; Kar, Satyabrata

doi:10.1016/j.neuroscience.2018.03.014

Cited by 21 publications

(21 citation statements)

References 63 publications

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“…Several intrinsic and extrinsic factors may trigger Aβ oligomerization. The N-terminal amino acid sequence has a big influence on self-aggregation of human Aβ into oligomers [45].…”

Section: Toxic Subpopulation Non-toxic Subpopulationmentioning

confidence: 99%

Oligomerization and Conformational Change Turn Monomeric β-Amyloid and Tau Proteins Toxic: Their Role in Alzheimer’s Pathogenesis

2020

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The structural polymorphism and the physiological and pathophysiological roles of two important proteins, β-amyloid (Aβ) and tau, that play a key role in Alzheimer’s disease (AD) are reviewed. Recent results demonstrate that monomeric Aβ has important physiological functions. Toxic oligomeric Aβ assemblies (AβOs) may play a decisive role in AD pathogenesis. The polymorph fibrillar Aβ (fAβ) form has a very ordered cross-β structure and is assumed to be non-toxic. Tau monomers also have several important physiological actions; however, their oligomerization leads to toxic oligomers (TauOs). Further polymerization results in probably non-toxic fibrillar structures, among others neurofibrillary tangles (NFTs). Their structure was determined by cryo-electron microscopy at atomic level. Both AβOs and TauOs may initiate neurodegenerative processes, and their interactions and crosstalk determine the pathophysiological changes in AD. TauOs (perhaps also AβO) have prionoid character, and they may be responsible for cell-to-cell spreading of the disease. Both extra- and intracellular AβOs and TauOs (and not the previously hypothesized amyloid plaques and NFTs) may represent the novel targets of AD drug research.

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“…Several intrinsic and extrinsic factors may trigger Aβ oligomerization. The N-terminal amino acid sequence has a big influence on self-aggregation of human Aβ into oligomers [45].…”

Section: Toxic Subpopulation Non-toxic Subpopulationmentioning

confidence: 99%

Oligomerization and Conformational Change Turn Monomeric β-Amyloid and Tau Proteins Toxic: Their Role in Alzheimer’s Pathogenesis

2020

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“…Such probes, in particular, are thioflavin T (ThT) and 1-anilino-8-naphthalene sulfonate (ANS). The benzothiazole dye ThT is the 'gold standard' for amyloid investigation [16][17][18][19][20][21]. This is due to a significant increase in fluorescence intensity and fluorescence lifetime of the dye accompanying its binding to amyloid fibrils in comparison to that of free ThT in aqueous solution which is caused by the molecular rotor nature of this dye [22,23].…”

Section: Introductionmentioning

confidence: 99%

Effect of the fluorescent probes ThT and ANS on the mature amyloid fibrils

Sulatsky

Sulatskaya

Povarova

et al. 2020

Prion

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Fluorescent probes thioflavin T (ThT) and 1-anilino-8-naphthalene sulfonate (ANS) are widely used to study amyloid fibrils that accumulate in the body of patients with serious diseases, such as Alzheimer's, Parkinson's, prion diseases, etc. However, the possible effect of these probes on amyloid fibrils is not well understood. In this work, we investigated the photophysical characteristics, structure, and morphology of mature amyloid fibrils formed from two model proteins, insulin and lysozyme, in the presence of ThT and ANS. It turned out that ANS affects the secondary structure of amyloids (shown for fibrils formed from insulin and lysozyme) and their fibers clusterization (valid for lysozyme fibrils), while ThT has no such effects. These results confirm the differences in the mechanisms of these dyes interaction with amyloid fibrils. Observed effect of ANS was explained by the electrostatic interactions between the dye molecule and cationic groups of amyloid-forming proteins (unlike hydrophobic binding of ThT) that induce amyloids conformational changes. This interaction leads to weakening repulsion between positive charges of amyloid fibrils and can promote their clusterization. It was shown that when fibrillogenesis conditions and, consequently, fibrils structure is changing, as well as during defragmentation of amyloids by ultrasonication, the influence of ANS to amyloids does not change, which indicates the universality of the detected effects. Based on the obtained results, it was concluded that ANS should be used cautiously for the study of amyloid fibrils, since this fluorescence probe have a direct effect on the object of study.

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“…Alzheimer's disease (AD) is a progressive and fatal neurodegenerative disease in which the deposition of extracellular senile plaques and the intracellular neurofibrillary tangles are the main hallmarks . The deposition or misfolding of amyloid‐β peptide (Aβ) is associated with the formation of senile plaques and therefore considered to be a key diagnostic target . Aβ is derived from the amyloid precursor protein by sequential cleavage, via β‐ and γ‐secretases.…”

Section: Introductionmentioning

confidence: 99%

“…[1][2][3] The deposition or misfolding of amyloid-β peptide (Aβ) is associated with the formation of senile plaques and therefore considered to be a key diagnostic target. [4,5] Aβ is derived from the amyloid precursor protein by sequential cleavage, via βand γ-secretases. Of the two main variants of the Aβ peptide (Aβ 40 and Aβ 42 ), Aβ 42 exhibits higher neuronal toxicity than Aβ 40 due to its tendency to rapidly form fibrils.…”

Section: Introductionmentioning

confidence: 99%

Engineering Versatile Nanoparticles for Near‐Infrared Light‐Tunable Drug Release and Photothermal Degradation of Amyloid β

Lai

Zhu

et al. 2020

Adv Funct Materials

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Nanomedicines that inhibit/disassemble amyloid β (Aβ) aggregates in Alzheimer's disease (AD) are highly desirable yet remain challenging. Therapeutic efficacy and systemic delivery of reported molecules and nanoparticles (NPs) are hampered by various challenges, including low biocompatibility, off‐target toxicity, and lack of specificity. Herein, a versatile NP is designed by integrating high Aβ‐binding affinity, stimuli‐responsive drug release, and photothermal degradation properties for efficient disassembly of Aβ. Near‐infrared (NIR)‐absorbing conjugated polymer PDPP3T‐O14 serves as a photothermal core while thermal‐responsive polymer 1,2‐dipalmitoyl‐sn‐glycero‐3‐phosphocholine at the outer layer as the NIR‐stimuli gatekeeper. Curcumin, an inhibitor of Aβ aggregation, is loaded into the NP with high encapsulation efficiency. The 5‐mer β‐sheet breaker peptides LPFFD (Leu‐Pro‐Phe‐Phe‐Asp) having high binding affinity toward Aβ are further anchored onto the surface of polyethylene glycol‐lipid shell for active Aβ‐targeting. The resultant NPs exhibit good Aβ‐targeting ability and obvious photothermal dissociation effect together with Aβ aggregation‐dependent fluorescence detection capability. Upon NIR laser irradiation, entrapped curcumin can be effectively released from the unconsolidated NPs to enhance the anti‐amyloid activity. In vitro studies demonstrate that the NPs dramatically lower Aβ‐induced cytotoxicity of PC12 cells, and therefore show great potential for the application in AD treatment.

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The Effects of N-terminal Mutations on β-amyloid Peptide Aggregation and Toxicity

Cited by 21 publications

References 63 publications

Oligomerization and Conformational Change Turn Monomeric β-Amyloid and Tau Proteins Toxic: Their Role in Alzheimer’s Pathogenesis

Oligomerization and Conformational Change Turn Monomeric β-Amyloid and Tau Proteins Toxic: Their Role in Alzheimer’s Pathogenesis

Effect of the fluorescent probes ThT and ANS on the mature amyloid fibrils

Engineering Versatile Nanoparticles for Near‐Infrared Light‐Tunable Drug Release and Photothermal Degradation of Amyloid β

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