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Effect of Cholesterol on Membrane Fluidity and Association of A? Oligomers and Subsequent Neuronal Damage: A Double-Edged Sword.

ABSTRACT: Background: The beta-amyloid peptide (A?) involved in Alzheimer's disease (AD) has been described to associate/aggregate on the cell surface disrupting the membrane through pore formation and breakage. However, molecular determinants involved for this interaction (e.g., some physicochemical properties of the cell membrane) are largely unknown. Since cholesterol is an important molecule for membrane structure and fluidity, we examined the effect of varying cholesterol content with the association and membrane perforation by A? in cultured hippocampal neurons. Methods: To decrease or increase the levels of cholesterol in the membrane we used methyl-?-cyclodextrin (M?CD) and M?CD/cholesterol, respectively. We analyzed if membrane fluidity was affected using generalized polarization (GP) imaging and the fluorescent dye di-4-ANEPPDHQ. Additionally membrane association and perforation was assessed using immunocytochemistry and electrophysiological techniques, respectively. Results: The results showed that cholesterol removal decreased the macroscopic association of A? to neuronal membranes (fluorescent-puncta/20 ?m: control = 18 ± 2 vs. M?CD = 10 ± 1, p < 0.05) and induced a facilitation of the membrane perforation by A? with respect to control cells (half-time for maximal charge transferred: control = 7.2 vs. M?CD = 4.4). Under this condition, we found an increase in membrane fluidity (46 ± 3.3% decrease in GP value, p < 0.001). On the contrary, increasing cholesterol levels incremented membrane rigidity (38 ± 2.7% increase in GP value, p < 0.001) and enhanced the association and clustering of A? (fluorescent-puncta/20 ?m: control = 18 ± 2 vs. M?CD = 10 ± 1, p < 0.01), but inhibited membrane disruption. Conclusion: Our results strongly support the significance of plasma membrane organization in the toxic effects of A? in hippocampal neurons, since fluidity can regulate distribution and insertion of the A? peptide in the neuronal membrane.

SUBMITTER: Fernandez-Perez EJ

PROVIDER: S-EPMC6085471 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Publications

Effect of Cholesterol on Membrane Fluidity and Association of Aβ Oligomers and Subsequent Neuronal Damage: A Double-Edged Sword.

Fernández-Pérez Eduardo J EJ Sepúlveda Fernando J FJ Peters Christian C Bascuñán Denisse D Riffo-Lepe Nicolás O NO González-Sanmiguel Juliana J Sánchez Susana A SA Peoples Robert W RW Vicente Benjamín B Aguayo Luis G LG

Frontiers in aging neuroscience 20180803

<b>Background:</b> The beta-amyloid peptide (Aβ) involved in Alzheimer's disease (AD) has been described to associate/aggregate on the cell surface disrupting the membrane through pore formation and breakage. However, molecular determinants involved for this interaction (e.g., some physicochemical properties of the cell membrane) are largely unknown. Since cholesterol is an important molecule for membrane structure and fluidity, we examined the effect of varying cholesterol content with the asso ...[more]

PMID: 30123122

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Project description:Prion diseases are infectious protein misfolding disorders of the central nervous system that result from misfolding of the cellular prion protein (PrPC) into the pathologic isoform PrPSc. Pathologic hallmarks of prion disease are depositions of pathological prion protein PrPSc, neuronal loss, spongiform degeneration and astrogliosis in the brain. Prion diseases affect human and animals, there is no effective therapy, and they invariably remain fatal. For a long time, neuronal loss was considered the sole reason for neurodegeneration in prion pathogenesis, and the contribution of non-neuronal cells like microglia and astrocytes was considered less important. Recent evidence suggests that neurodegeneration during prion pathogenesis is a consequence of a complex interplay between neuronal and non-neuronal cells in the brain, but the exact role of these non-neuronal cells during prion pathology is still elusive. Astrocytes are non-neuronal cells that regulate brain homeostasis under physiological conditions. However, astrocytes can deposit PrPSc aggregates and propagate prions in prion-infected brains. Additionally, sub-populations of reactive astrocytes that include neurotrophic and neurotoxic species have been identified, differentially expressed in the brain during prion infection. Revealing the exact role of astrocytes in prion disease is hampered by the lack of in vitro models of prion-infected astrocytes. Recently, we established a murine astrocyte cell line persistently infected with mouse-adapted prions, and showed how such astrocytes differentially process various prion strains. Considering the complexity of the role of astrocytes in prion pathogenesis, we need more in vitro and in vivo models for exploring the contribution of sub-populations of reactive astrocytes, their differential regulation of signaling cascades, and the interaction with neurons and microglia during prion pathogenesis. This will help to establish novel in vivo models and define new therapeutic targets against prion diseases. In this review, we will discuss the complex role of astrocytes in prion disease, the existing experimental resources, the challenges to analyze the contribution of astrocytes in prion disease pathogenesis, and future strategies to improve the understanding of their role in prion disease.

Dataset Information

Effect of Cholesterol on Membrane Fluidity and Association of A? Oligomers and Subsequent Neuronal Damage: A Double-Edged Sword.

Publications

Effect of Cholesterol on Membrane Fluidity and Association of Aβ Oligomers and Subsequent Neuronal Damage: A Double-Edged Sword.

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