HSF1 physically neutralizes amyloid oligomers to empower overgrowth and bestow neuroprotection.
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ABSTRACT:
SUBMITTER: Tang Z
PROVIDER: S-EPMC7673739 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Background and aimsUnnatural self-organizing biomimetic polymers (foldamers) emerged as promising materials for biomolecule recognition and inhibition. Our goal was to construct multivalent foldamer-dendrimer conjugates which wrap the synaptotoxic β-amyloid (Aβ) oligomers with high affinity through their helical foldamer tentacles. Oligomeric Aβ species play pivotal role in Alzheimer's disease, therefore recognition and direct inhibition of this undruggable target is a great current challenge.Methods and resultsShort helical β-peptide foldamers with designed secondary structures and side chain chemistry patterns were applied as potential recognition segments and their binding to the target was tested with NMR methods (saturation transfer difference and transferred-nuclear Overhauser effect). Helices exhibiting binding in the µM region were coupled to a tetravalent G0-PAMAM dendrimer. In vitro biophysical (isothermal titration calorimetry, dynamic light scattering, transmission electron microscopy and size-exclusion chromatography) and biochemical tests (ELISA and dot blot) indicated the tight binding between the foldamer conjugates and the Aβ oligomers. Moreover, a selective low nM interaction with the low molecular weight fraction of the Aβ oligomers was found. Ex vivo electrophysiological experiments revealed that the new material rescues the long-term potentiation from the toxic Aβ oligomers in mouse hippocampal slices at submicromolar concentration.ConclusionsThe combination of the foldamer methodology, the fragment-based approach and the multivalent design offers a pathway to unnatural protein mimetics that are capable of specific molecular recognition, and has already resulted in an inhibitor for an extremely difficult target.
| S-EPMC3408453 | biostudies-literature
Project description:Brain accumulation of soluble oligomers of the amyloid-β peptide (AβOs) is increasingly considered a key early event in the pathogenesis of Alzheimer's disease (AD). A variety of AβO species have been identified, both in vitro and in vivo, ranging from dimers to 24mers and higher order oligomers. However, there is no consensus in the literature regarding which AβO species are most germane to AD pathogenesis. Antibodies capable of specifically recognizing defined subpopulations of AβOs would be a valuable asset in the identification, isolation, and characterization of AD-relevant AβO species. Here, we report the characterization of a human single chain antibody fragment (scFv) denoted NUsc1, one of a number of scFvs we have identified that stringently distinguish AβOs from both monomeric and fibrillar Aβ. NUsc1 readily detected AβOs previously bound to dendrites in cultured hippocampal neurons. In addition, NUsc1 blocked AβO binding and reduced AβO-induced neuronal oxidative stress and tau hyperphosphorylation in cultured neurons. NUsc1 further distinguished brain extracts from AD-transgenic mice from wild type (WT) mice, and detected endogenous AβOs in fixed AD brain tissue and AD brain extracts. Biochemical analyses indicated that NUsc1 targets a subpopulation of AβOs with apparent molecular mass greater than 50 kDa. Results indicate that NUsc1 targets a particular AβO species relevant to AD pathogenesis, and suggest that NUsc1 may constitute an effective tool for AD diagnostics and therapeutics.
| S-EPMC5752625 | biostudies-literature
Project description:Alzheimer's disease (AD) is the most prevalent but still incurable neurodegenerative form of dementia. Early diagnosis and intervention are crucial for delaying the onset and progression of the disease. We herein report a novel fluoro-substituted cyanine, F-SLOH, which exhibits good A? oligomer selectivity with a high binding affinity, attributed to the synergistic effect of strong ?-? stacking and intermolecular CH···O and CH···F interactions. The selectivity towards the A? oligomers in the brain was ascertained by in vitro labelling on tissue sections and in vivo labelling through the systemic administration of F-SLOH in 7 month APP/PS1 double transgenic (Tg) and APP/PS1/Tau triple Tg mouse models. F-SLOH also shows remarkably effective inhibition on A? aggregation and highly desirable neuroprotective effects against A?-induced toxicities, including the inhibition of ROS production and Ca2+ influx. Its excellent blood-brain barrier (BBB) penetrability and low bio-toxicity further support its tremendous potential as a novel theranostic agent for both early diagnosis and therapy of AD.
| S-EPMC5858019 | biostudies-literature
Project description:The spontaneous assembly of proteins into amyloid fibrils is a phenomenon central to many increasingly common and currently incurable human disorders, including Alzheimer's and Parkinson's diseases. Oligomeric species form transiently during this process and not only act as essential intermediates in the assembly of new filaments but also represent major pathogenic agents in these diseases. While amyloid fibrils possess a common, defining set of physicochemical features, oligomers, by contrast, appear much more diverse, and their commonalities and differences have hitherto remained largely unexplored. Here, we use the framework of chemical kinetics to investigate their dynamical properties. By fitting experimental data for several unrelated amyloidogenic systems to newly derived mechanistic models, we find that oligomers present with a remarkably wide range of kinetic and thermodynamic stabilities but that they possess two properties that are generic: they are overwhelmingly nonfibrillar, and they predominantly dissociate back to monomers rather than maturing into fibrillar species. These discoveries change our understanding of the relationship between amyloid oligomers and amyloid fibrils and have important implications for the nature of their cellular toxicity.
| S-EPMC7275774 | biostudies-literature
Project description:Amyloid oligomers are believed to play important causal roles in many types of amyloid-related degenerative diseases. Many different laboratories have reported amyloid oligomers that differ in size, morphology, toxicity, and method of preparation or purification, raising the question of the structural relationships among these oligomer preparations. The structural plasticity that has been reported to occur in amyloids formed from the same protein sequence indicates that it is quite possible that different oligomer preparations may represent distinct structural variants. In view of the difficulty in determining the precise structure of amyloids, conformation- and epitope-specific antibodies may provide a facile means of classifying amyloid oligomer structures. Conformation-dependent antibodies that recognize generic epitopes that are specifically associated with distinct aggregation states of many different amyloid-forming sequences indicate that there are at least two fundamentally distinct types of amyloid oligomers: fibrillar and prefibrillar oligomers. Classification of amyloid oligomers according to their underlying structures may be a more useful and rational approach than relying on differences in size and morphology.
| S-EPMC2573087 | biostudies-other
Project description:The link between the size of soluble amyloid beta (Abeta) oligomers and their toxicity to rat cerebellar granule cells (CGC) was investigated. Variation in conditions during in vitro oligomerization of Abeta(1-42) resulted in peptide assemblies with different particle size as measured by atomic force microscopy and confirmed by dynamic light scattering and fluorescence correlation spectroscopy. Small oligomers of Abeta(1-42) with a mean particle z-height of 1-2 nm exhibited propensity to bind to phospholipid vesicles and they were the most toxic species that induced rapid neuronal necrosis at submicromolar concentrations whereas the bigger aggregates (z-height above 4-5 nm) did not bind vesicles and did not cause detectable neuronal death. A similar neurotoxic pattern was also observed in primary cultures of cortex neurons whereas Abeta(1-42) oligomers, monomers and fibrils were non-toxic to glial cells in CGC cultures or macrophage J774 cells. However, both oligomeric forms of Abeta(1-42) induced reduction of neuronal cell densities in the CGC cultures.
| S-EPMC2853175 | biostudies-literature
Project description:Amyloid-beta (Aβ)-induced neurotoxicity is a major contributor to the pathologies associated with Alzheimer's disease (AD). The formation of reactive oxygen species (ROS), an early response induced by the peptide and oligomeric derivatives of Aβ, plays a significant role in effecting cellular pathogenesis. Here we employ particularly toxic forms of Aβ with cultured primary cortical/hippocampal neurons to elicit ROS and drive cellular dysfunction. To prevent and even reverse such effects, we utilized a cell-penetrating, peroxisome-targeted, protein biologic--called CAT-SKL. We show the recombinant enzyme enters neurons, reverses Aβ-induced oxidative stress, and increases cell viability. Dramatic restorative effects on damaged neuronal processes were also observed. In addition, we used DNA microarrays to determine Aβ's effects on gene expression in neurons, as well as the ability of CAT-SKL to modify such Aβ-induced expression profiles. Our results suggest that CAT-SKL, a targeted antioxidant, may represent a new therapeutic approach for treatment of disorders, like Alzheimer's disease, that are driven through oxidative stress. Preclinical testing is ongoing.
| S-EPMC4021325 | biostudies-literature
Project description:Although amyloid fibers are found in neurodegenerative diseases, evidence points to soluble oligomers of amyloid-forming proteins as the cytotoxic species. Here, we establish that our preparation of toxic amyloid-?(1-42) (Abeta42) fibrillar oligomers (TABFOs) shares with mature amyloid fibrils the cross-? structure, in which adjacent ?-sheets adhere by interpenetration of protein side chains. We study the structure and properties of TABFOs by powder X-ray diffraction, EM, circular dichroism, FTIR spectroscopy, chromatography, conformational antibodies, and celluar toxicity. In TABFOs, Abeta42 molecules stack into short protofilaments consisting of pairs of helical ?-sheets that wrap around each other to form a superhelix. Wrapping results in a hole along the superhelix axis, providing insight into how Abeta may form pathogenic amyloid pores. Our model is consistent with numerous properties of Abeta42 fibrillar oligomers, including heterogenous size, ability to seed new populations of fibrillar oligomers, and fiber-like morphology.
| S-EPMC3356606 | biostudies-literature
Project description:Oligomeric amyloid-? 1-42 (A?-42) peptides are considered to be the most toxic species connected to the occurrence of Alzheimer's disease. However, not all aggregation conditions promote oligomer formation in vitro, raising the question whether oligomer formation in vivo also requires a specific suitable cellular environment. We recently found that interaction with neuronal membranes initiates aggregation of A?-42 and neuronal uptake. Our data suggest that small molecules in the extracellular space can facilitate the formation of membrane-active A?-42 oligomers. We analyzed the early stage of A?-42 aggregation in the presence of glucose and sucrose and found that these sugars strongly favor A?-42 oligomer formation. We characterized oligomers by dynamic light scattering, atomic force microscopy, immuno-transmission electron microscopy and fluorescence cross correlation spectroscopy. We found that A?-42 spontaneously and rapidly forms low molecular weight oligomers in the presence of sugars. Slightly acidic pH (6.7-7) greatly favors oligomer formation when compared to the extracellular physiological pH (7.4). Circular dichroism demonstrated that these A?-42 oligomers did not adopt a ?-sheet structure. Unstructured oligomeric A?-42 interacted with membrane bilayers of giant unilamellar vesicles (GUV) and neuronal model cells, facilitated cellular uptake of A?-42, and inhibition of mitochondrial activity. Our data therefore suggest that elevated concentrations of glucose within the range observed in diabetic individuals (10 mM) facilitate the formation of membrane-active A?-42 oligomers.
| S-EPMC5654640 | biostudies-literature
Project description:Amyloid oligomers play a central role in Alzheimer's and other amyloid diseases, and yet the structures of these heterogeneous and unstable species are not well understood. To better understand the structures of oligomers formed by amyloid-? peptide (A?), we have incorporated a key amyloidogenic region of A? into a macrocyclic peptide that stabilizes oligomers and facilitates structural elucidation by X-ray crystallography. This paper reports the crystallographic structures of oligomers and oligomer assemblies formed by a macrocycle containing the A?(15-23) nonapeptide. The macrocycle forms hydrogen-bonded ?-sheets that assemble into cruciform tetramers consisting of eight ?-strands in a two-layered assembly. Three of the cruciform tetramers assemble into a triangular dodecamer. These oligomers further assemble in the lattice to form hexagonal pores. Molecular modeling studies suggest that the natural A? peptide can form similar oligomers and oligomer assemblies. The crystallographic and molecular modeling studies suggest the potential for interaction of the oligomers with cell membranes and provide insights into the role of oligomers in amyloid diseases.
| S-EPMC3787202 | biostudies-literature