AFM investigation of the aggregation behavior of Alzheimer's disease A&amp;#x03B2; peptides

Ungureanu, Andreea-Alexandra; Benilova, Iryna; Bael, Margriet J. Van; Haesendonck, Chris Van; Bartic, Carmen

doi:10.1109/nano.2012.6322180

Cited by 3 publications

(5 citation statements)

References 6 publications

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“…After incubating Aβ 42 (25 μM) at 37 °C for 48 h, serried and entangled fibrils were observed (Figure 2a), consistent with literature results. 48,49 The morphological characteristics changed little in the sample with pCB (Figure 2b). Coincubating curcumin at 5 to 25 μM with Aβ 42 also led to the formation of fibrous aggregates, though Aβ 42 fibers became shorter and less tangled, the lengths and amount of fibril decreased with increasing curcumin concentration (Figure 2d), consistent with previous studies.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

Self-Assembled Curcumin–Poly(carboxybetaine methacrylate) Conjugates: Potent Nano-Inhibitors against Amyloid β-Protein Fibrillogenesis and Cytotoxicity

2018

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Fibrillogenesis of amyloid β-protein (Aβ) is a pathological hallmark of Alzheimer's disease, so inhibition of Aβ aggregation is considered as an important strategy for the precaution and treatment of AD. Curcumin (Cur) has been recognized as an effective inhibitor of Aβ fibrillogenesis, but its potential application is limited by its poor bioavailability. Herein, we proposed to conjugate Cur to a zwitterionic polymer, poly(carboxybetaine methacrylate) (pCB), and synthesized three Cur@pCB conjugates of different degrees of substitution (DS, 1.9-2.9). Cur@pCB conjugates self-assembled into nanogels of 120-190 nm. The inhibition effects of Cur@pCB conjugates on the fibrillation and cytotoxicity of Aβ was investigated by extensive biophysical and biological analyses. Thioflavin T fluorescence assays and atomic force microscopic observations revealed that the Cur@pCB conjugates were much more efficient than molecular curcumin on inhibiting Aβ fibrillation, and cytotoxicity assays also indicated the same tendency. Of the three conjugates, Cur1@pCB of the lowest DS (1.97) exhibited the best performance; 5 μM Cur1@pCB functioned similarly with 25 μM free curcumin. Moreover, 5 μM Cur1@pCB increased the cell viability by 43% but free curcumin at the same concentration showed little effect. It is considered that the highly hydrated state of the zwitterionic polymers resulted in the superiority of Cur@pCB over free curcumin. Namely, the dense hydration layer on the conjugates strongly stabilized the bound Aβ on curcumin anchored on the polymer, suppressing the conformational transition of the protein to β-sheet-rich structures. This was demonstrated by circular dichroism spectroscopy, in which Cur1@pCB was proven to be the strongest in the three conjugates. The research has thus revealed a new function of zwitterionic polymer pCBMA and provided new insights into the development of more potent nanoinhibitors for suppressing Aβ fibrillogenesis and cytotoxicity.

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Section: ■ Results and Discussionmentioning

confidence: 99%

Self-Assembled Curcumin–Poly(carboxybetaine methacrylate) Conjugates: Potent Nano-Inhibitors against Amyloid β-Protein Fibrillogenesis and Cytotoxicity

2018

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“…Prior to evaluating the neuronal responses to Aβ40 and Aβ42 oligomers, we characterized the species formed by these peptides after several hours of aggregation in Tris-EDTA (Trisaminomethane - Ethylene-Diamine-Tetraacetic Acid) buffer. The two peptides have previously been reported to have different aggregation behaviors, as determined using Thioflavin T (ThT) measurements, AFM snap-shots and theoretical calculations 8 41 42 . Moreover, our previous in vitro and in vivo studies have shown that the smaller species formed by Aβ42 are more efficient at triggering toxic mechanisms in neurons than Aβ40 8 .…”

Section: Resultsmentioning

confidence: 99%

“…Mechanical forces are known to play an important role in processes such as gene expression, ion-channel gating and vesicular transport 41 . The mechanical properties of membranes define the way in which cells respond to such forces and therefore their ability to perform these functions.…”

Section: Discussionmentioning

confidence: 99%

“…For instance, the active transport of vesicles in neurons is regulated by presynaptic membrane tension 40 , the activity of ion channels is dependent on membrane deformations 39 , and changes in the elasticity of the substantia nigra have been shown to occur in patients in the early stages of Parkinson’s Disease 61 . Although little is known about the mechanobiology of the brain 41 one can expect that changes in the neuronal membrane elasticity or stiffness might directly induce functional changes related to neurodegeneration in AD, regardless of the mechanism underlying such changes.…”

Section: Discussionmentioning

confidence: 99%

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Amyloid beta oligomers induce neuronal elasticity changes in age-dependent manner: a force spectroscopy study on living hippocampal neurons

Ungureanu

Benilova

Krylychkina

et al. 2016

Sci Rep

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Small soluble species of amyloid-beta (Aβ) formed during early peptide aggregation stages are responsible for several neurotoxic mechanisms relevant to the pathology of Alzheimer’s disease (AD), although their interaction with the neuronal membrane is not completely understood. This study quantifies the changes in the neuronal membrane elasticity induced by treatment with the two most common Aβ isoforms found in AD brains: Aβ40 and Aβ42. Using quantitative atomic force microscopy (AFM), we measured for the first time the static elastic modulus of living primary hippocampal neurons treated with pre-aggregated Aβ40 and Aβ42 soluble species. Our AFM results demonstrate changes in the elasticity of young, mature and aged neurons treated for a short time with the two Aβ species pre-aggregated for 2 hours. Neurons aging under stress conditions, showing aging hallmarks, are the most susceptible to amyloid binding and show the largest decrease in membrane stiffness upon Aβ treatment. Membrane stiffness defines the way in which cells respond to mechanical forces in their environment and has been shown to be important for processes such as gene expression, ion-channel gating and neurotransmitter vesicle transport. Thus, one can expect that changes in neuronal membrane elasticity might directly induce functional changes related to neurodegeneration.

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“…The four nanomechanical signatures delineate the mechanical properties of cells/neurons from different aspects and correlate with different biological activities. E is predominantly linked with the mechanical properties of the cellular membrane/actin cortex, which plays important roles in many neuronal activities such as vesicular transport and ion-channel gating/action potential firing . The transport of vesicles in neurons is regulated by presynaptic membrane tension, and the activity of ion channels is influenced by membrane deformation. , K cell is used to assess the change of the intracellular osmotic pressure caused by the intracellular Ca 2+ concentration.…”

Section: Resultsmentioning

confidence: 99%

Nanomechanical Profiling of Aβ42 Oligomer-Induced Biological Changes in Single Hippocampus Neurons

Tang

et al. 2023

ACS Nano

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Understanding how Aβ42 oligomers induce changes in neurons from a mechanobiological perspective has important implications in neuronal dysfunction relevant to neurodegenerative diseases. However, it remains challenging to profile the mechanical responses of neurons and correlate the mechanical signatures to the biological properties of neurons given the structural complexity of cells. Here, we quantitatively investigate the nanomechanical properties of primary hippocampus neurons upon exposure to Aβ42 oligomers at the single neuron level by using atomic force microscopy (AFM). We develop a method termed heterogeneity-load-unload nanomechanics (HLUN), which exploits the AFM force spectra in the whole loading–unloading cycle, allowing comprehensive profiling of the mechanical properties of living neurons. We extract four key nanomechanical parameters, including the apparent Young’s modulus, cell spring constant, normalized hysteresis, and adhesion work, that serve as the nanomechanical signatures of neurons treated with Aβ42 oligomers. These parameters are well-correlated with neuronal height increase, cortical actin filament strengthening, and calcium concentration elevation. Thus, we establish an HLUN method-based AFM nanomechanical analysis tool for single neuron study and build an effective correlation between the nanomechanical profile of the single neurons and the biological effects triggered by Aβ42 oligomers. Our finding provides useful information on the dysfunction of neurons from the mechanobiological perspective.

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AFM investigation of the aggregation behavior of Alzheimer's disease Aβ peptides

Cited by 3 publications

References 6 publications

Self-Assembled Curcumin–Poly(carboxybetaine methacrylate) Conjugates: Potent Nano-Inhibitors against Amyloid β-Protein Fibrillogenesis and Cytotoxicity

Self-Assembled Curcumin–Poly(carboxybetaine methacrylate) Conjugates: Potent Nano-Inhibitors against Amyloid β-Protein Fibrillogenesis and Cytotoxicity

Amyloid beta oligomers induce neuronal elasticity changes in age-dependent manner: a force spectroscopy study on living hippocampal neurons

Nanomechanical Profiling of Aβ42 Oligomer-Induced Biological Changes in Single Hippocampus Neurons

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