Magnetic Resonance Studies of β-Amyloid Peptides

The deposition of senile plaques is a characteristic event in the progression of Alzheimer's disease (AD). Associated with the progression of the disease, the main component of the deposited material, the β-amyloid peptide (Aβ), undergoes a structural transition and a toxic gain of function. For this reason, extensive structural studies of Aβ and Aβ fragments have been carried out in order to determine the relationship between neurotoxicity and conformational changes of the peptide that lead to fibril formation. NMR studies in aqueous solution and in membrane-mimicking environments are reviewed, and include the effects of temperature, pH, and metal ions on Aβ structure. In addition, electron paramagnetic resonance (EPR) studies of Aβ in model membranes and the effect of metals of Aβ are discussed and demonstrate the pleiomorphic nature of the peptide. The contradictory results obtained from the various experiments are a result of studying different fragments of Aβ and illustrate the importance of studying the full-length peptide.

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Paper-Based Detection Device for Alzheimer’s Disease—Detecting β-amyloid Peptides (1–42) in Human Plasma

Diagnostics ◽

10.3390/diagnostics10050272 ◽

2020 ◽

Vol 10 (5) ◽

pp. 272

Author(s):

Wei-Hsuan Sung ◽

Jung-Tung Hung ◽

Yu-Jen Lu ◽

Chao-Min Cheng

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Operating Time ◽

Amyloid Peptide ◽

Buffer System ◽

Amyloid Peptides ◽

Β Amyloid ◽

Β Amyloid Peptide ◽

Short Operating Time ◽

Tremendous Impact

The diagnosis of Alzheimer’s disease (AD) is frequently missed or delayed in clinical practice. To remedy this situation, we developed a screening, paper-based (P-ELISA) platform to detect β-amyloid peptide 1–42 (Aβ42) and provide rapid results using a small volume, easily accessible plasma sample instead of cerebrospinal fluid. The protocol outlined herein only requires 3 μL of sample per well and a short operating time (i.e., only 90 min). The detection limit of Aβ42 is 63.04 pg/mL in a buffer system. This P-ELISA-based approach can be used for early, preclinical stage AD screening, including screening for amnestic mild cognitive impairment (MCI) due to AD. It may also be used for treatment and stage monitoring purposes. The implementation of this approach may provide tremendous impact for an afflicted population and may well prompt additional and expanded efforts in both academic and commercial communities.

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β-Amyloid peptide does not bind iron after fixation but senile plaques do

Neurobiology of Aging ◽

10.1016/s0197-4580(00)82480-x ◽

2000 ◽

Vol 21 ◽

pp. 57

Author(s):

Malia M. Dixon ◽

Stephen R. Robinson

Keyword(s):

Senile Plaques ◽

Amyloid Peptide ◽

Β Amyloid ◽

Β Amyloid Peptide

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Inhibition of fibril formation in β-amyloid peptide by a novel series of benzofurans

Biochemical Journal ◽

10.1042/bj3400283 ◽

1999 ◽

Vol 340 (1) ◽

pp. 283-289 ◽

Cited By ~ 66

Author(s):

David R. HOWLETT ◽

Amanda E. PERRY ◽

Fiona GODFREY ◽

Jane E. SWATTON ◽

Kevin H. JENNINGS ◽

...

Keyword(s):

Binding Assay ◽

Close Correlation ◽

Fibril Formation ◽

Biologically Active ◽

Amyloid Peptide ◽

Binding Assays ◽

Nmr Studies ◽

Β Amyloid ◽

Β Amyloid Peptide ◽

Self Aggregation

A series of benzofuran derivatives have been identified as inhibitors of fibril formation in the β-amyloid peptide. The activity of these compounds has been assessed by a novel fibril-formation-specific immunoassay and for their effects on the production of a biologically active fibril product. The inhibition afforded by the compounds seems to be associated with their binding to β-amyloid, as identified by scintillation proximity binding assay. Binding assays and NMR studies also indicate that the inhibition is associated with self-aggregation of the compounds. There is a close correlation between the activity of the benzofurans as inhibitors of fibril formation and their ability to bind to β-amyloid. Non-benzofuran inhibitors of the fibril formation process do not seem to bind to the same site on the β-amyloid molecule as the benzofurans. Thus a specific recognition site might exist for benzofurans on β-amyloid, binding to which seems to interfere with the ability of the peptide to form fibrils.

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Tocotrienol decreases β-amyloid mediated toxicity in Caenorhabditis elegans model of Alzheimer’s disease

10.1101/2020.04.13.040105 ◽

2020 ◽

Author(s):

Chee Wah Yuen ◽

Mardani Abdul Halim ◽

Vikneswaran Murugaiyah ◽

Nazalan Najimudin ◽

Ghows Azzam

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Caenorhabditis Elegans ◽

Senile Plaques ◽

Amyloid Peptide ◽

Model Of Alzheimer’S Disease ◽

Aβ Aggregation ◽

Anti Oxidant ◽

Β Amyloid ◽

Β Amyloid Peptide

AbstractAlzheimer’s disease (AD) is a neurological disease caused by the accumulation of extracellular senile plaques consisting of β-amyloid peptide (Aβ) in the brain. A transgenic Caenorhabditis elegans which demonstrated paralysis due to the expression of human beta amyloid Aβ42 gene was used to study the anti-paralysis effect of mixed tocotrienols. The content of the mixed tocotrienols were 12.1% α-, 2.7% β-, 18.6% γ-, and 8.1% δ-tocotrienols. Mixed tocotrienols significantly delayed the Aβ-induced paralysis in the transgenic nematode and exhibited anti-oxidant properties towards Aβ-generated oxidative stress. The mixture also presented potent inhibitory activities against Aβ aggregation with an IC50 value of 600 ng/ml. It is concluded that mixed tocotrienols could potentially serve as a new therapeutic candidate for AD.

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Mechanism of Cellular Formation and In Vivo Seeding Effects of Hexameric β-amyloid Assemblies

10.21203/rs.3.rs-550136/v1 ◽

2021 ◽

Author(s):

Céline Vrancx ◽

Devkee M Vadukul ◽

Nuria Suelves ◽

Sabrina Contino ◽

Ludovic D'Auria ◽

...

Keyword(s):

Senile Plaques ◽

Amyloid Peptide ◽

Secretase Activity ◽

Aβ Aggregation ◽

Cellular Context ◽

Β Amyloid ◽

Β Amyloid Peptide ◽

Aβ Generation

Abstract The β-amyloid peptide (Aβ) is the main constituent of senile plaques, a typical hallmark of Alzheimer’s disease (AD). Monomeric Aβ is generated through sequential processing of the amyloid precursor protein (APP), with a final step involving γ-secretase activity. In AD, Aβ monomers assemble in oligomers and ultimately fibrils depositing in plaques. Importantly, Aβ toxicity appears related to its soluble oligomeric intermediates. In particular, recombinant Aβ studies described Aβ hexamers as critical oligomeric nuclei. We recently identified hexameric Aβ assemblies in a cellular model, and revealed their ability to enhance recombinant Aβ aggregation in vitro. Here, we assessed the contribution of similar hexameric-like Aβ assemblies to the development of amyloid pathology. We report their early presence in both transgenic mice brains exhibiting human Aβ pathology and cerebrospinal fluid of AD patients, suggesting hexameric Aβ as a putative novel AD biomarker. Using isolated cell-derived hexameric Aβ, we report the potential of these assemblies to seed other human Aβ species, resulting in neuronal toxicity in vitro and amyloid deposition aggravation in vivo. In order to identify key contributors to their formation in a cellular context, we investigated the role of presenilin-1 (PS1) and presenilin-2 (PS2) in the formation of hexameric-like Aβ assemblies. As catalytic subunits of the γ-secretase complex, PS1 and PS2 can differentially participate in Aβ generation. Using CRISPR-Cas9-modified neuronal-like cell lines knockdown for each of the two presenilins, we present experimental evidence suggesting a direct link between the PS2-dependent pathway and the release of hexameric-like Aβ assemblies in extracellular vesicles.

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Dominant and differential deposition of distinct β-amyloid peptide species, AβN3(pE), in senile plaques

Neuron ◽

10.1016/0896-6273(95)90301-1 ◽

1995 ◽

Vol 14 (2) ◽

pp. 457-466 ◽

Cited By ~ 373

Author(s):

Takaomi C Saido ◽

Takeshi Iwatsubo ◽

David M.A Mann ◽

Hiroyuki Shimada ◽

Yasuo Ihara ◽

...

Keyword(s):

Senile Plaques ◽

Amyloid Peptide ◽

Β Amyloid ◽

Β Amyloid Peptide

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Conformational Characterization of Native and L17A/F19A-Substituted Dutch-Type β-Amyloid Peptides

International Journal of Molecular Sciences ◽

10.3390/ijms21072571 ◽

2020 ◽

Vol 21 (7) ◽

pp. 2571 ◽

Cited By ~ 1

Author(s):

Kai-Cyuan He ◽

Yi-Ru Chen ◽

Chu-Ting Liang ◽

Shi-Jie Huang ◽

Chung-Ying Tzeng ◽

...

Keyword(s):

Sodium Dodecyl ◽

Amyloid Peptide ◽

Genetic Mutations ◽

Wild Type ◽

Amyloid Peptides ◽

Aβ Aggregation ◽

Nuclear Magnetic Spectroscopy ◽

Β Amyloid ◽

Β Amyloid Peptide

Some mutations which occur in the α/β-discordant region (resides 15 to 23) of β-amyloid peptide (Aβ) lead to familial Alzheimer’s disease (FAD). In vitro studies have shown that these genetic mutations could accelerate Aβ aggregation. We recently showed that mutations in this region could alter the structural propensity, resulting in a different aggregative propensity of Aβ. Whether these genetic mutations display similar effects remains largely unknown. Here, we characterized the structural propensity and aggregation kinetics of Dutch-type Aβ40 (Aβ40(E22Q)) and its L17A/F19A-substituted mutant (Aβ40(L17A/F19A/E22Q)) using circular dichroism spectroscopy, nuclear magnetic spectroscopy, and thioflavin T fluorescence assay. In comparison with wild-type Aβ40, we found that Dutch-type mutation, unlike Artic-type mutation (E22G), does not reduce the α-helical propensity of the α/β-discordant region in sodium dodecyl sulfate micellar solution. Moreover, we found that Aβ40(L17A/F19A/E22Q) displays a higher α-helical propensity of the α/β-discordant region and a slower aggregation rate than Aβ40(E22Q), suggesting that the inhibition of aggregation might be via increasing the α-helical propensity of the α/β-discordant region, similar to that observed in wild-type and Artic-type Aβ40. Taken together, Dutch-type and Artic-type mutations adopt different mechanisms to promote Aβ aggregation, however, the L17A/F19A mutation could increase the α-helical propensities of both Dutch-type and Artic-type Aβ40 and inhibit their aggregation.

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