Membrane Mechanical Properties Regulate the Effect of Strain on Spontaneous Electrophysiology in Human iPSC-Derived Neurons

Bianchi, Fabio; Pereno, Valerio; George, Julian H.; Thompson, Mark S.; Ye, Hua

doi:10.1016/j.neuroscience.2019.02.014

Cited by 10 publications

(10 citation statements)

References 57 publications

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“…The enhanced stiffness of naked mole-rat lipid bilayer membranes is most likely due to the increased cholesterol, which is known to increase membrane rigidity. 27…”

Section: Lipid Bilayers Formed From Naked Mole-rat Brain-derived Totamentioning

confidence: 99%

Lipid membranes from naked mole-rat brain lipids are cholesterol-rich, highly phase-separated, and sensitive to amyloid-induced damage

Frankel

Davies

Bhushan

et al. 2020

Preprint

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Naked mole-rats do not develop neurodegenerative diseases associated with ageing and their brains are devoid of amyloid plaques. However, even the young naked mole-rat brain contains high concentrations of amyloid beta peptide. Thus, the question arises, how do naked mole-rat brain cell membranes survive in this amyloid rich environment? In this work we examine the composition, phase behaviour, and amyloid beta interactions of naked mole-rat brain lipids. Relative to mouse, naked mole-rat brain lipids are rich in cholesterol and contain less sphingomyelin, the sphingomyelin present being of a characteristic short chain length. We find that naked mole-rat brain lipid membranes exhibit an extremely high degree of phase separation, consistent with the membrane pacemaker hypothesis of ageing, with the liquid ordered phase occupying up to 80 % of the supported lipid bilayer. Exposure of mouse brain lipids to human amyloid beta at physiologically relevant concentrations leads to small, well-defined "footprints", whereby the amyloid beta has sunk into the membrane. Under the same exposure regime, the naked mole-rat brain lipid membranes are destroyed, leaving only membrane fragments in place of the intact membrane. These results suggest that naked mole-rats have likely developed additional neuroprotective mechanisms to limit cellular damage because by considering lipids alone brain tissue should not be able to survive in such a toxic environment.

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“…The enhanced stiffness of naked mole-rat lipid bilayer membranes is most likely due to the increased cholesterol, which is known to increase membrane rigidity. 27…”

Section: Lipid Bilayers Formed From Naked Mole-rat Brain-derived Totamentioning

confidence: 99%

Lipid membranes from naked mole-rat brain lipids are cholesterol-rich, highly phase-separated, and sensitive to amyloid-induced damage

Frankel

Davies

Bhushan

et al. 2020

Preprint

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“…Recently, an experimental work has tried to quantify axonal membrane strains induced by the deformation applied to a cell culture as a whole (104). Differences between applied strains and membrane strains were reported.…”

Section: Discussionmentioning

confidence: 99%

Localized Axolemma Deformations Suggest Mechanoporation as Axonal Injury Trigger

et al. 2020

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Morphological choicesAs now reported in the main text of the manuscript, given the axon cross-section and the proposed MTs densities (Bray and Bunge 1981, Fadic et al. 1985, Malbouisson et al. 1985) 19 rows of MTs were included in the axon RV, each containing two randomly placed discontinuities. The same approach was used in Peter and Mofrad (2012), Lazarus et al. (2015), Soheilypour et al. (2015). Mechanical properties of the MTs have been very well identifies by previous studies. Material properties These filaments represent the stiffest part of the cytoskeleton and the Youngs' modulus (E=830 MPa) was derived by Zhang et al. (2014) with a numerical approach and was in extremely good agreement with experiments by de Pablo et al (2003)where MTs are locally probed. In the latter study, older bending experiments (which estimate a modulus E=1 to 1.2 GPa) were considered to overestimate the material properties of MTs because they usually probe length scales much longer than the one necessary to assess material properties. Being these filaments far stiffer then the remainder of our model, it can be said that a slightly stiffer modulus would not affect the localization of strains on the membrane. Tau proteins:Morphological choices Cross-connection between microtubules (MTs) and between neurofilaments (NFs) and MTs were quantified in a seminal study by Hirokawa (1982). There, MTs crosslinks were found to be less abundant than those between neurofilaments, which were reported having a 30-50 nm spacing. Inspecting the microscopy images in the same publication, a spacing of 120 nm was chosen for our model. Previous studies have also shown, through a sensitivity study, that tau protein density does not influence the energy associated with MTs stretching. Material propertiesCompared to the MTs, the material properties of these filaments are far less studied. The properties that we chose are based on previous studies by Ahmadzadeh et al (2014,2015). In these studies the viscoelastic characteristic of these cross-links was derived from previous experimental studies. While the spring stiffness is in the range of previously tested motor proteins (kinesin stiffness = uN/m ), we agree that its viscous component is the biggest assumption behind our model, which would however would affect mostly the microtubule Bray, D. and Bunge, M.B., 1981. Serial analysis of microtubules in cultured rat sensory axons. ., 2003. Deformation and collapse of microtubules on the nanometer scale. Physical review letters, 91(9), p.098101. Hirokawa, N., 1982. Cross-linker system between neurofilaments, microtubules and membranous organelles in frog axons revealed by the quick-freeze, deep-etching method. The Journal of cell biology, 94(1), pp.129-142. Ahmadzadeh, H., Smith, D.H. and Shenoy, V.B., 2014. Viscoelasticity of tau proteins leads to strain rate-dependent breaking of microtubules during axonal stretch injury: predictions from a mathematical model. Biophysical journal, 106(5), pp.1123-1133. Ahmadzadeh, H., Smith, D.H. and Shenoy, V.B., 2015. Mech...

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“…Recently, an experimental work has tried to quantify axonal membrane strains induced by the deformation applied to a cell culture as a whole. 100 Differences between applied strains and membrane strains were reported. However, it must be noted that these discrepancies may mostly be due to the non-alignment between applied load and axons’ directions within the culture.…”

Section: Discussionmentioning

confidence: 99%

Localized axolemma deformations suggest mechanoporation as axonal injury trigger

Montanino

Saeedimasine

Villa

et al. 2019

Preprint

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13Traumatic brain injuries are a leading cause of morbidity and mortality worldwide. With 14 almost 50% of traumatic brain injuries being related to axonal damage, understanding the 15 nature of cellular level impairment is crucial. Experimental observations have so far led to the 16 formulation of conflicting theories regarding the cellular primary injury mechanism. 17 Disruption of the axolemma, or alternatively cytoskeletal damage has been suggested mainly 18 as injury trigger. However, mechanoporation thresholds of generic membranes seem not to 19 overlap with the axonal injury deformation range and microtubules appear too stiff and too 20 weakly connected to undergo mechanical breaking. Here, we aim to shed a light on the 21 mechanism of primary axonal injury, bridging finite element and molecular dynamics 22 simulations. Despite the necessary level of approximation, our models can accurately 23 describe the mechanical behavior of the unmyelinated axon and its membrane. More 24 importantly, they give access to quantities that would be inaccessible with an experimental 25 approach. We show that in a typical injury scenario, the axonal cortex sustains deformations 26 large enough to entail pore formation in the adjoining lipid bilayer. The observed axonal 27 deformation of 10-12% agree well with the thresholds proposed in the literature for axonal 28 injury and, above all, allow us to provide quantitative evidences that do not exclude pore 29 formation in the membrane as a result of trauma. Our findings bring to an increased 30 knowledge of axonal injury mechanism that will have positive implications for the prevention 31 and treatment of brain injuries. 33 34Traumatic brain injury (TBI) is defined as "an alteration in brain function, or other evidence 2 of brain pathology, caused by an external force". 1 In 2013 approximately 2.8 million TBI-3 related emergency department visits, hospitalization, and deaths occurred in the United 4 States. 2 In a recent study reporting the epidemiology of TBI in Europe, Peeters and coworkers 5 analyzed data from 28 studies on 16 European countries and reported an average mortality 6 rate of ≈ 11 per 100,000 population over an incidence rate of 262 per 100,000 population per 7year. 3 Diffuse axonal injury (DAI), a multifocal damage to white matter axons, is the most 8 common consequence of TBIs of all severities including mild TBIs or concussions. 4 Invisible 9 to conventional brain imaging, DAI can only be histologically diagnosed and its hallmark is 10 the presence of axonal swellings or retraction balls observable under microscopic 11 examination. 5 12 13Considerable research effort has been put into the understanding of the primary effects of 14 trauma onto the neurons. To define an axonal injury trigger, nervous tissues and neuronal 15 cultures have been subjected to dynamic loads leading to several hypotheses regarding the 16 cell injury mechanism. Mechanoporation (i.e. the generation of membrane pores due to 17 mechanical deformation) of the axolemma has been his...

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Membrane Mechanical Properties Regulate the Effect of Strain on Spontaneous Electrophysiology in Human iPSC-Derived Neurons

Cited by 10 publications

References 57 publications

Lipid membranes from naked mole-rat brain lipids are cholesterol-rich, highly phase-separated, and sensitive to amyloid-induced damage

Lipid membranes from naked mole-rat brain lipids are cholesterol-rich, highly phase-separated, and sensitive to amyloid-induced damage

Localized Axolemma Deformations Suggest Mechanoporation as Axonal Injury Trigger

Localized axolemma deformations suggest mechanoporation as axonal injury trigger

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