scholarly journals The genetic landscape for amyloid beta fibril nucleation accurately discriminates familial Alzheimer's disease mutations

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Mireia Seuma ◽  
Andre Faure ◽  
Marta Badia ◽  
Ben Lehner ◽  
Benedetta Bolognesi
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Genetic Variation ◽  
Amyloid Beta ◽  
Human Disease ◽  
Amyloid Fibril ◽  
Aβ Peptide ◽  
Disease Mutations ◽  
Genetic Landscape ◽  
A Cell

Plaques of the amyloid beta (Aβ) peptide are a pathological hallmark of Alzheimer's Disease (AD), the most common form of dementia. Mutations in Aβ also cause familial forms of AD (fAD). Here we use deep mutational scanning to quantify the effects of >14,000 mutations on the aggregation of Aβ. The resulting genetic landscape reveals mechanistic insights into fibril nucleation, including the importance of charge and gatekeeper residues in the disordered region outside of the amyloid core in preventing nucleation. Strikingly, unlike computational predictors and previous measurements, the empirical nucleation scores accurately identify all known dominant fAD mutations in AB42, genetically validating that the mechanism of nucleation in a cell-based assay is likely to be very similar to the mechanism that causes the human disease. These results provide the first comprehensive atlas of how mutations alter the formation of any amyloid fibril and a resource for the interpretation of genetic variation in Aβ.

scholarly journals The genetic landscape for amyloid beta fibril nucleation accurately discriminates familial Alzheimer’s disease mutations

2020 ◽  
Author(s):  
Mireia Seuma ◽  
Andre Faure ◽  
Marta Badia ◽  
Ben Lehner ◽  
Benedetta Bolognesi
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Beta ◽  
Amyloid Fibrils ◽  
List Type ◽  
Familial Alzheimer’S Disease ◽  
Disease Mutations ◽  
Genetic Landscape ◽  
Familial Alzheimer's Disease

AbstractAmyloid fibrils are associated with many human diseases but how mutations alter the propensity of proteins to form fibrils has not been comprehensively investigated and is not well understood. Alzheimer’s Disease (AD) is the most common form of dementia with amyloid plaques of the amyloid beta (Aß) peptide a pathological hallmark of the disease. Mutations in Aß also cause familial forms of AD (fAD). Here we use deep mutational scanning to quantify the effects of >14,000 mutations on the aggregation of Aß. The resulting genetic landscape reveals fundamental mechanistic insights into fibril nucleation, including the importance of charge and gatekeeper residues in the disordered region outside of the amyloid core in preventing nucleation. Strikingly, unlike computational predictors and previous measurements, the in vivo nucleation scores accurately identify all known dominant fAD mutations, validating this simple cell-based assay as highly relevant to the human genetic disease and suggesting accelerated fibril nucleation is the ultimate cause of fAD. Our results provide the first comprehensive map of how mutations alter the formation of any amyloid fibril and a validated resource for the interpretation of genetic variation in Aß.HighlightsFirst comprehensive map of how mutations alter the propensity of a protein to form amyloid fibrils.Charge and gatekeeper residues in the disordered N-terminus of amyloid beta prevent fibril nucleation.Rates of nucleation in a cell-based assay accurately identify the mutations that cause dominant familial Alzheimer’s disease.The combination of deep mutational scanning and human genetics provides a general strategy to quantify the disease-relevance of in vitro and in vivo assays.

Molecular dynamic studies of amyloid-beta interactions with curcumin and Cu2+ ions

2015 ◽  
Vol 69 (9) ◽  
Author(s):  
Stanislav Kozmon ◽  
Igor Tvaroška
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Molecular Dynamics ◽  
Transition Metals ◽  
Metal Ions ◽  
Molecular Dynamic ◽  
Amyloid Beta ◽  
Md Simulations ◽  
Aβ Peptide ◽  
Dynamic Studies

AbstractAmyloid-beta (Aβ) peptide readily forms aggregates that are associated with Alzheimer’s disease. Transition metals play a key role in this process. Recently, it has been shown that curcumin (CUA), a polyphenolic phytochemical, inhibits the aggregation of Aβ peptide. However, interactions of Aβ peptide with metal ions or CUA are not entirely clear. In this work, molecular dynamics (MD) simulations were carried out to clear the nature of interactions between the 42-residue Aβ peptide (Aβ-42) and Cu

scholarly journals Familial Alzheimer’s Disease Mutations in Presenilin Generate Amyloidogenic Aβ Peptide Seeds

Neuron ◽  
2016 ◽  
Vol 90 (2) ◽  
pp. 410-416 ◽  
Author(s):  
Sarah Veugelen ◽  
Takashi Saito ◽  
Takaomi C. Saido ◽  
Lucía Chávez-Gutiérrez ◽  
Bart De Strooper
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Aβ Peptide ◽  
Familial Alzheimer’S Disease ◽  
Disease Mutations ◽  
Familial Alzheimer's Disease

Insight into molecular interactions of Aβ peptide and gelatinase from Enterococcus faecalis: a molecular modeling approach

RSC Advances ◽  
2015 ◽  
Vol 5 (14) ◽  
pp. 10488-10496 ◽  
Author(s):  
Chidambar B. Jalkute ◽  
Sagar H. Barage ◽  
Kailas D. Sonawane
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Molecular Modeling ◽  
Enterococcus Faecalis ◽  
Amyloid Beta ◽  
Molecular Interactions ◽  
Aβ Peptide ◽  
Aβ Peptides ◽  
Modeling Approach ◽  
Insight Into

Alzheimer's disease is characterized by the presence of extracellular deposition of amyloid beta (Aβ) peptides.

scholarly journals The amyloid-beta forming tripeptide cleavage mechanism of γ-secretase

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
David M Bolduc ◽  
Daniel R Montagna ◽  
Matthew C Seghers ◽  
Michael S Wolfe ◽  
Dennis J Selkoe
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amino Acid ◽  
Amyloid Beta ◽  
Aβ Peptides ◽  
Enzyme Substrate ◽  
Disease Mutations ◽  
Initial Substrate ◽  
Binding Pockets ◽  
Amino Acid Binding

γ-secretase is responsible for the proteolysis of amyloid precursor protein (APP) into short, aggregation-prone amyloid-beta (Aβ) peptides, which are centrally implicated in the pathogenesis of Alzheimer’s disease (AD). Despite considerable interest in developing γ-secretase targeting therapeutics for the treatment of AD, the precise mechanism by which γ-secretase produces Aβ has remained elusive. Herein, we demonstrate that γ-secretase catalysis is driven by the stabilization of an enzyme-substrate scission complex via three distinct amino-acid-binding pockets in the enzyme’s active site, providing the mechanism by which γ-secretase preferentially cleaves APP in three amino acid increments. Substrate occupancy of these three pockets occurs after initial substrate binding but precedes catalysis, suggesting a conformational change in substrate may be required for cleavage. We uncover and exploit substrate cleavage preferences dictated by these three pockets to investigate the mechanism by which familial Alzheimer’s disease mutations within APP increase the production of pathogenic Aβ species.

scholarly journals Natural Products Targeting Amyloid Beta in Alzheimer’s Disease

2021 ◽  
Vol 22 (5) ◽  
pp. 2341
Author(s):  
Joo-Hee Lee ◽  
Na-Hyun Ahn ◽  
Su-Bin Choi ◽  
Youngeun Kwon ◽  
Seung-Hoon Yang
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Trial ◽  
Natural Products ◽  
Amyloid Beta ◽  
Conformational Changes ◽  
Aβ Peptide ◽  
Aβ Peptides ◽  
Peptide Formation ◽  
Current Clinical Trial

Alzheimer’s disease (AD) is a neurodegenerative disease characterized by severe brain damage and dementia. There are currently few therapeutics to treat this disease, and they can only temporarily alleviate some of the symptoms. The pathogenesis of AD is mainly preceded by accumulation of abnormal amyloid beta (Aβ) aggregates, which are toxic to neurons. Therefore, modulation of the formation of these abnormal aggregates is strongly suggested as the most effective approach to treat AD. In particular, numerous studies on natural products associated with AD, aiming to downregulate Aβ peptides and suppress the formation of abnormal Aβ aggregates, thus reducing neural cell death, are being conducted. Generation of Aβ peptides can be prevented by targeting the secretases involved in Aβ-peptide formation (secretase-dependent). Additionally, blocking the intra- and intermolecular interactions of Aβ peptides can induce conformational changes in abnormal Aβ aggregates, whereby the toxicity can be ameliorated (structure-dependent). In this review, AD-associated natural products which can reduce the accumulation of Aβ peptides via secretase- or structure-dependent pathways, and the current clinical trial states of these products are discussed.

scholarly journals Identification of amyloid beta in small extracellular vesicles via Raman spectroscopy

2021 ◽  
Author(s):  
Meruyert Imanbekova ◽  
Sorina Suarasan ◽  
Tatu Rojalin ◽  
Rachel Mizenko ◽  
Silvia Hilt ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Raman Spectroscopy ◽  
Extracellular Vesicles ◽  
Amyloid Beta ◽  
Aβ Peptide

The hallmark of Alzheimer’s disease (AD) pathogenesis is believed to be the production and deposition of amyloid-beta (Aβ) peptide into extracellular plaques. Existing research indicates that extracellular vesicles (EVs) can...

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