scholarly journals Molecular structure of a prevalent amyloid-β fibril polymorph from Alzheimer’s disease brain tissue

2020 ◽  
Author(s):  
Ujjayini Ghosh ◽  
Kent R. Thurber ◽  
Wai-Ming Yau ◽  
Robert Tycko
Keyword(s):  
Molecular Structure ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Molecular Conformation ◽  
Amyloid Β ◽  
Cryo Electron Microscopy ◽  
Nmr Data ◽  
Fibril Structure ◽  
Aggregation Inhibitors ◽  
Aβ Fibrils

AbstractAmyloid-β (Aβ) fibrils exhibit self-propagating, molecular-level polymorphisms that may underlie variations in clinical and pathological characteristics of Alzheimer’s disease. We report the molecular structure of a specific brain-derived polymorph that has been identified as the most prevalent polymorph of 40-residue Aβ fibrils in cortical tissue of Alzheimer’s disease patients. This structure, developed from cryo-electron microscopy and supported by solid state NMR data, differs qualitatively from all previously described Aβ fibril structures, both in its molecular conformation and its organization of cross-β subunits. Knowledge of this brain-derived fibril structure may contribute to the development of structure-specific amyloid imaging agents and aggregation inhibitors with greater diagnostic and therapeutic utility.

scholarly journals Molecular structure of a prevalent amyloid-β fibril polymorph from Alzheimer's disease brain tissue

2021 ◽  
Vol 118 (4) ◽  
pp. e2023089118 ◽  
Author(s):  
Ujjayini Ghosh ◽  
Kent R. Thurber ◽  
Wai-Ming Yau ◽  
Robert Tycko
Keyword(s):  
Molecular Structure ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Β ◽  
Molecular Conformations ◽  
Layered Architecture ◽  
Fibril Structure ◽  
Aggregation Inhibitors ◽  
Aβ Fibrils ◽  
Β Sheet

Amyloid-β (Aβ) fibrils exhibit self-propagating, molecular-level polymorphisms that may contribute to variations in clinical and pathological characteristics of Alzheimer’s disease (AD). We report the molecular structure of a specific fibril polymorph, formed by 40-residue Aβ peptides (Aβ40), that is derived from cortical tissue of an AD patient by seeded fibril growth. The structure is determined from cryogenic electron microscopy (cryoEM) images, supplemented by mass-per-length (MPL) measurements and solid-state NMR (ssNMR) data. Previous ssNMR studies with multiple AD patients had identified this polymorph as the most prevalent brain-derived Aβ40 fibril polymorph from typical AD patients. The structure, which has 2.8-Å resolution according to standard criteria, differs qualitatively from all previously described Aβ fibril structures, both in its molecular conformations and its organization of cross-β subunits. Unique features include twofold screw symmetry about the fibril growth axis, despite an MPL value that indicates three Aβ40 molecules per 4.8-Å β-sheet spacing, a four-layered architecture, and fully extended conformations for molecules in the central two cross-β layers. The cryoEM density, ssNMR data, and MPL data are consistent with β-hairpin conformations for molecules in the outer cross-β layers. Knowledge of this brain-derived fibril structure may contribute to the development of structure-specific amyloid imaging agents and aggregation inhibitors with greater diagnostic and therapeutic utility.

Development of curcumin-based amyloid β aggregation inhibitors for Alzheimer's disease using the SAR matrix approach

2021 ◽  
pp. 116357
Author(s):  
Rohmad Yudi Utomo ◽  
Yasunobu Asawa ◽  
Satoshi Okada ◽  
Hyun Seung Ban ◽  
Atsushi Yoshimori ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Β ◽  
Matrix Approach ◽  
Aggregation Inhibitors

scholarly journals Functionalized Mesoporous Silicas Direct Structural Polymorphism of Amyloid-β Fibrils

2020 ◽  
Author(s):  
Michael J. Lucas ◽  
Henry S. Pan ◽  
Eric J. Verbeke ◽  
Lauren J. Webb ◽  
David W. Taylor ◽  
...  
Keyword(s):  
Electron Microscopy ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
De Novo ◽  
Amyloid Β ◽  
Mesoporous Silicas ◽  
Aggregation Kinetics ◽  
Central Feature ◽  
Relative Population ◽  
Aβ Fibrils

AbstractThe aggregation of Amyloid-β (Aβ) is associated with the onset of Alzheimer’s Disease (AD) and involves a complex kinetic pathway as monomers self-assemble into fibrils. A central feature of amyloid fibrils is the existence of multiple structural polymorphs, which complicates the development of disease-relevant structure-function relationships. Developing these relationships requires new methods to control fibril structure. In this work, we demonstrate that mesoporous silicas (SBA-15) functionalized with hydrophobic (SBA-PFDTS) and hydrophilic groups (SBA-PEG) direct the aggregation kinetics and resulting structure of Aβ1-40 fibrils. The hydrophilic SBA-PEG had little effect on amyloid kinetics while as-synthesized and hydrophobic SBA-PFDTS accelerated aggregation kinetics. Subsequently, we quantified the relative population of fibril structures formed in the presence of each material using electron microscopy. Fibrils formed from Aβ1-40 exposed to SBA-PEG were structurally similar to control fibrils. In contrast, Aβ1-40 incubated with SBA-15 or SBA-PFDTS formed fibrils with shorter cross-over distances that were more structurally representative of fibrils found in AD patient-derived samples. Overall, these results suggest that mesoporous silicas and other exogenous materials are promising scaffolds for the de novo production of specific fibril polymorphs of Aβ1-40 and other amyloidogenic proteins.Significance StatementA major challenge in understanding the progression of Alzheimer’s Disease lies in the various fibril structures, or polymorphs, adopted by Amyloid-β (Aβ). Heterogenous fibril populations may be responsible for different disease phenotypes and growing evidence suggests that Aβ fibrils formed in vitro are structurally distinct from patient-derived fibrils. To help bridge this gap, we used surface-functionalized mesoporous silicas to influence the formation of Aβ1-40 fibrils and evaluated the distribution of resulting fibril polymorphs using electron microscopy (EM). We found that silicas modified with hydrophobic surfaces resulted in fibril populations with shorter cross-over distances that are more representative of Aβ fibrils observed ex vivo. Overall, our results indicate that mesoporous silicas may be leveraged for the production of specific Aβ polymorphs.

Proton Stimulation Targeting Plaque Magnetite Reduces Amyloid-β Plaque and Iron Redox Toxicity and Improves Memory in an Alzheimer’s Disease Mouse Model

2021 ◽  
pp. 1-16
Author(s):  
Seung-Jun Seo ◽  
Won-Seok Chang ◽  
Jae-Geun Jeon ◽  
Younshick Choi ◽  
EunHo Kim ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Function ◽  
Mouse Brain ◽  
Amyloid Β ◽  
Amyloid Plaque ◽  
Plaque Burden ◽  
Protein Matrix ◽  
Entrance Dose ◽  
Aβ Fibrils

Background: The coexistence of magnetite within protein aggregates in the brain is a typical pathologic feature of Alzheimer’s disease (AD), and the formation of amyloid-β (Aβ) plaques induces critical impairment of cognitive function. Objective: This study aimed to investigate the therapeutic effect of proton stimulation (PS) targeting plaque magnetite in the transgenic AD mouse brain. Methods: A proton transmission beam was applied to the whole mouse brain at a single entrance dose of 2 or 4 Gy to test the effect of disruption of magnetite-containing Aβ plaques by electron emission from magnetite. The reduction in Aβ plaque burden and the cognitive function of the PS-treated mouse group were assayed by histochemical analysis and memory tests, respectively. Aβ-magnetite and Aβ fibrils were treated with PS to investigate the breakdown of the amyloid protein matrix. Results: Single PS induced a 48–87%reduction in both the amyloid plaque burden and ferrous-containing magnetite level in the early-onset AD mouse brain while saving normal tissue. The overall Aβ plaque burden (68–82%) and (94–97%) hippocampal magnetite levels were reduced in late onset AD mice that showed improvements in cognitive function after PS compared with untreated AD mice (p <  0.001). Analysis of amyloid fibrils after exposure to a single 2 or 4 Gy proton transmission beam demonstrated that the protein matrix was broken down only in magnetite-associated Aβ fibrils. Conclusion: Single PS targeting plaque magnetite effectively decreases the amyloid plaque burden and the ferrous-containing magnetite level, and this effect is useful for memory recovery.

scholarly journals Quinacrine directly dissociates amyloid plaques in the brain of 5XFAD transgenic mouse model of Alzheimer’s disease

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Sohui Park ◽  
Hye Yun Kim ◽  
Hyun-A Oh ◽  
Jisu Shin ◽  
In Wook Park ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Molecular Weight ◽  
Transgenic Mice ◽  
Cortical Neurons ◽  
Amyloid Β ◽  
Synaptic Function ◽  
Western Blots ◽  
Aβ Fibrils ◽  
The Brain

AbstractAlzheimer’s disease (AD) is the most common type of dementia characterized by the abnormal accumulation of amyloid-β (Aβ) in the brain. Aβ misfolding is associated with neuroinflammation and synaptic dysfunction, leading to learning and memory deficits. Therefore, Aβ production and aggregation have been one of the most popular drug targets for AD. Failures of drug candidates regulating the aforementioned Aβ cascade stimulated development of immunotherapy agents for clearance of accumulated Aβ in the brain. Here, we report that quinacrine, a blood–brain barrier penetrating antimalarial chemical drug, dissociates Aβ plaques in the brain of AD transgenic mice. When co-incubated with pre-formed Aβ fibrils, quinacrine decreased thioflavin T-positive β-sheets in vitro, on top of its inhibitory function on the fibril formation. We confirmed that quinacrine induced dissociation of high-molecular-weight Aβ aggregates into low-molecular-weight species by dot blots in association with size cut-off filtrations. Quinacrine was then administered to adult 5XFAD transgenic mice via weekly intravenous injections for 6 weeks, and we found a significant reduction of Aβ plaques and astrocytosis in their cortex and hippocampus. In western blots of quinacrine-administered mouse brains, amelioration of AD-related biomarkers, glial fibrillary acidic protein, postsynaptic protein 95, phosphorylated cAMP response element-binding protein, phosphorylated c-Jun N-terminal kinase were observed. Lastly, quinacrine-stimulated dissociation of misfolded aggregates induced recovery of synaptic function associated with Aβ in excitatory post-synaptic current recordings of primary rat cortical neurons treated with Aβ aggregates and quinacrine. Collectively, quinacrine can directly dissociate Aβ fibrils and alleviate decreased synaptic functions.

scholarly journals Biflavonoid-Induced Disruption of Hydrogen Bonds Leads to Amyloid-b Disaggregation

2021 ◽  
Vol 22 (6) ◽  
pp. 2888
Author(s):  
Peter K. Windsor ◽  
Stephen P. Plassmeyer ◽  
Dominic S. Mattock ◽  
Jonathan C. Bradfield ◽  
Erika Y. Choi ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Hydrogen Bond ◽  
Amyloid Β ◽  
Structural Basis ◽  
Hydroxyl Groups ◽  
Dependent Manner ◽  
Dynamic Simulations ◽  
Hydrogen Bond Formation ◽  
Aβ Fibrils

Deposition of amyloid β (Aβ) fibrils in the brain is a key pathologic hallmark of Alzheimer’s disease. A class of polyphenolic biflavonoids is known to have anti-amyloidogenic effects by inhibiting aggregation of Aβ and promoting disaggregation of Aβ fibrils. In the present study, we further sought to investigate the structural basis of the Aβ disaggregating activity of biflavonoids and their interactions at the atomic level. A thioflavin T (ThT) fluorescence assay revealed that amentoflavone-type biflavonoids promote disaggregation of Aβ fibrils with varying potency due to specific structural differences. The computational analysis herein provides the first atomistic details for the mechanism of Aβ disaggregation by biflavonoids. Molecular docking analysis showed that biflavonoids preferentially bind to the aromatic-rich, partially ordered N-termini of Aβ fibril via the p–p interactions. Moreover, docking scores correlate well with the ThT EC50 values. Molecular dynamic simulations revealed that biflavonoids decrease the content of β-sheet in Aβ fibril in a structure-dependent manner. Hydrogen bond analysis further supported that the substitution of hydroxyl groups capable of hydrogen bond formation at two positions on the biflavonoid scaffold leads to significantly disaggregation of Aβ fibrils. Taken together, our data indicate that biflavonoids promote disaggregation of Aβ fibrils due to their ability to disrupt the fibril structure, suggesting biflavonoids as a lead class of compounds to develop a therapeutic agent for Alzheimer’s disease.

scholarly journals Modulation of β-Amyloid Fibril Formation in Alzheimer’s Disease by Microglia and Infection

2020 ◽  
Vol 13 ◽  
Author(s):  
Madeleine R. Brown ◽  
Sheena E. Radford ◽  
Eric W. Hewitt
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Fibril ◽  
Amyloid Β ◽  
Aβ Peptides ◽  
Aβ Amyloid ◽  
Aβ Fibrils ◽  
The Brain

Amyloid plaques are a pathological hallmark of Alzheimer’s disease. The major component of these plaques are highly ordered amyloid fibrils formed by amyloid-β (Aβ) peptides. However, whilst Aβ amyloid fibril assembly has been subjected to detailed and extensive analysis in vitro, these studies may not reproduce how Aβ fibrils assemble in the brain. This is because the brain represents a highly complex and dynamic environment, and in Alzheimer’s disease multiple cofactors may affect the assembly of Aβ fibrils. Moreover, in vivo amyloid plaque formation will reflect the balance between the assembly of Aβ fibrils and their degradation. This review explores the roles of microglia as cofactors in Aβ aggregation and in the clearance of amyloid deposits. In addition, we discuss how infection may be an additional cofactor in Aβ fibril assembly by virtue of the antimicrobial properties of Aβ peptides. Crucially, by understanding the roles of microglia and infection in Aβ amyloid fibril assembly it may be possible to identify new therapeutic targets for Alzheimer’s disease.

Recent advances in the design and applications of amyloid-β peptide aggregation inhibitors for Alzheimer’s disease therapy

2019 ◽  
Vol 11 (6) ◽  
pp. 901-925 ◽  
Author(s):  
Safura Jokar ◽  
Saeedeh Khazaei ◽  
Hossein Behnammanesh ◽  
Amir Shamloo ◽  
Mostafa Erfani ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Β ◽  
Amyloid Β Peptide ◽  
Peptide Aggregation ◽  
Recent Advances ◽  
Disease Therapy ◽  
Aggregation Inhibitors

scholarly journals Small-Molecule Amyloid Beta-Aggregation Inhibitors in Alzheimer's Disease Drug Development

2019 ◽  
Vol 01 (01) ◽  
pp. e22-e32
Author(s):  
Sharmin Reza Chowdhury ◽  
Fangzhou Xie ◽  
Jinxin Gu ◽  
Lei Fu
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Small Molecules ◽  
Small Molecule ◽  
Disease Process ◽  
Amyloid Β ◽  
Symptomatic Improvement ◽  
Starting Point ◽  
Aβ Aggregation ◽  
Aggregation Inhibitors

AbstractAlzheimer's disease (AD) is still an incurable neurodegenerative disease that causes dementia. AD changes the brain function that, over time, impairs memory and diminishes judgment and reasoning ability. Pathophysiology of AD is complex. Till now the cause of AD remains unknown, but risk factors include family history and genetic predisposition. The drugs previously approved for AD treatment do not modify the disease process and only provide symptomatic improvement. Over the past few decades, research has led to significant progress in the understanding of the disease, leading to several novel strategies that may modify the disease process. One of the major developments in this direction is the amyloid β (Aβ) aggregation. Small molecules could block the initial stages of Aβ aggregation, which could be the starting point for the design and development of new AD drugs in the near future. In this review we summarize the most promising small-molecule Aβ-aggregation inhibitors including natural compounds, novel small molecules, and also those are in clinical trials. Moreover, we briefly summarized some reported docking studies of small-molecule Aβ aggregation inhibitors. These will give us an idea about the chemical features required to design novel small molecules with anti-Aβ aggregation properties.

scholarly journals Specific aromatic foldamers potently inhibit spontaneous and seeded Aβ42 and Aβ43 fibril assembly

2014 ◽  
Vol 464 (1) ◽  
pp. 85-98 ◽  
Author(s):  
Katelyn M. Seither ◽  
Heather A. McMahon ◽  
Nikita Singh ◽  
Hejia Wang ◽  
Mimi Cushman-Nick ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Β ◽  
The Self ◽  
Aβ Peptides ◽  
Aβ Fibrils ◽  
Therapeutic Utility

We report specific aromatic foldamers that inhibit fibrillization by amyloid-β (Aβ) peptides connected with Alzheimer's disease. One foldamer inhibits formation of toxic Aβ-species as well as the self-templating activity of Aβ fibrils, properties that could have therapeutic utility.

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