Endocytosis Is a Key Mode of Interaction between Extracellular β-Amyloid and the Cell Membrane

Shi, Jing-Ming; Zhu, Li; Lan, Xi; Zhao, Duan-Wei; He, Yongjun; Sun, Zhengqi; Wu, Di; Li, Haiyun

doi:10.1016/j.bpj.2020.07.035

Cited by 11 publications

(7 citation statements)

References 65 publications

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“…The conclusions of this work were revealed to be of extreme importance to understanding the main mechanism implicated in AD pathogenesis since humans and macaque brains share significant similarities [ 18 ]. Additionally, the mechanistic studies performed in different neuronal cell lines have indicated that the exogenous addition of the oligomeric forms of Aβ(1-40)/(1-42) to the extracellular medium leads to the internalization of Aβ in neurons, showing an intraneuronal subcellar distribution between mitochondria, lysosomes/endosomes, and the ER [ 19 , 20 , 21 , 22 , 23 ].…”

Section: Introductionmentioning

confidence: 99%

Internalized Amyloid-β (1-42) Peptide Inhibits the Store-Operated Calcium Entry in HT-22 Cells

Poejo

Orantos-Aguilera

Martı́n-Romero

et al. 2022

IJMS

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Dysregulation in calcium signaling pathways plays a major role in the initiation of Alzheimer’s disease (AD) pathogenesis. Accumulative experimental evidence obtained with cellular and animal models, as well as with AD brain samples, points out the high cytotoxicity of soluble small oligomeric forms of amyloid-β peptides (Aβ) in AD. In recent works, we have proposed that Aβ-calmodulin (CaM) complexation may play a major role in neuronal Ca2+ signaling, mediated by CaM-binding proteins (CaMBPs). STIM1, a recognized CaMBP, plays a key role in store-operated calcium entry (SOCE), and it has been shown that the SOCE function is diminished in AD, resulting in the instability of dendric spines and enhanced amyloidogenesis. In this work, we show that 2 and 5 h of incubation with 2 μM Aβ(1-42) oligomers of the immortalized mouse hippocampal cell line HT-22 leads to the internalization of 62 ± 11 nM and 135 ± 15 nM of Aβ(1-42), respectively. Internalized Aβ(1-42) oligomers colocalize with the endoplasmic reticulum (ER) and co-immunoprecipitated with STIM1, unveiling that this protein is a novel target of Aβ. Fluorescence resonance energy transfer measurements between STIM1 tagged with a green fluorescent protein (GFP) and Aβ(1-42)-HiLyte™-Fluor555 show that STIM1 can bind nanomolar concentrations of Aβ(1-42) oligomers at a site located close to the CaM-binding site in STIM1. Internalized Aβ(1-42) produced dysregulation of the SOCE in the HT-22 cells before a sustained alteration of cytosolic Ca2+ homeostasis can be detected, and is elicited by only 2 h of incubation with 2 μM Aβ(1-42) oligomers. We conclude that Aβ(1-42)-induced SOCE dysregulation in HT-22 cells is caused by the inhibitory modulation of STIM1, and the partial activation of ER Ca2+-leak channels.

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Section: Introductionmentioning

confidence: 99%

Internalized Amyloid-β (1-42) Peptide Inhibits the Store-Operated Calcium Entry in HT-22 Cells

Poejo

Orantos-Aguilera

Martı́n-Romero

et al. 2022

IJMS

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“…Sodium azide (NaN 3 ) is used to inhibit energy-dependent endocytosis by disrupting ATP production. The intracellular fluorescence intensity of cells treated with NaN 3 decreased by approximately 26% compared to the control group, confirming that the cellular uptake of rhApoE/Cou-6/Aβ-CN-PMs was moderately energy-dependent [ 44 , 45 ].…”

Section: Resultsmentioning

confidence: 82%

Novel brain-targeted nanomicelles for anti-glioma therapy mediated by the ApoE-enriched protein corona in vivo

Xin

Liu

et al. 2021

J Nanobiotechnol

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Background The interactions between nanoparticles (NPs) and plasma proteins form a protein corona around NPs after entering the biological environment, which provides new biological properties to NPs and mediates their interactions with cells and biological barriers. Given the inevitable interactions, we regard nanoparticle‒protein interactions as a tool for designing protein corona-mediated drug delivery systems. Herein, we demonstrate the successful application of protein corona-mediated brain-targeted nanomicelles in the treatment of glioma, loading them with paclitaxel (PTX), and decorating them with amyloid β-protein (Aβ)-CN peptide (PTX/Aβ-CN-PMs). Aβ-CN peptide, like the Aβ1–42 peptide, specifically binds to the lipid-binding domain of apolipoprotein E (ApoE) in vivo to form the ApoE-enriched protein corona surrounding Aβ-CN-PMs (ApoE/PTX/Aβ-CN-PMs). The receptor-binding domain of the ApoE then combines with low-density lipoprotein receptor (LDLr) and LDLr-related protein 1 receptor (LRP1r) expressed in the blood–brain barrier and glioma, effectively mediating brain-targeted delivery. Methods PTX/Aβ-CN-PMs were prepared using a film hydration method with sonication, which was simple and feasible. The specific formation of the ApoE-enriched protein corona around nanoparticles was characterized by Western blotting analysis and LC–MS/MS. The in vitro physicochemical properties and in vivo anti-glioma effects of PTX/Aβ-CN-PMs were also well studied. Results The average size and zeta potential of PTX/Aβ-CN-PMs and ApoE/PTX/Aβ-CN-PMs were 103.1 nm, 172.3 nm, 7.23 mV, and 0.715 mV, respectively. PTX was efficiently loaded into PTX/Aβ-CN-PMs, and the PTX release from rhApoE/PTX/Aβ-CN-PMs exhibited a sustained-release pattern in vitro. The formation of the ApoE-enriched protein corona significantly improved the cellular uptake of Aβ-CN-PMs on C6 cells and human umbilical vein endothelial cells (HUVECs) and enhanced permeability to the blood–brain tumor barrier in vitro. Meanwhile, PTX/Aβ-CN-PMs with ApoE-enriched protein corona had a greater ability to inhibit cell proliferation and induce cell apoptosis than taxol. Importantly, PTX/Aβ-CN-PMs exhibited better anti-glioma effects and tissue distribution profile with rapid accumulation in glioma tissues in vivo and prolonged median survival of glioma-bearing mice compared to those associated with PMs without the ApoE protein corona. Conclusions The designed PTX/Aβ-CN-PMs exhibited significantly enhanced anti-glioma efficacy. Importantly, this study provided a strategy for the rational design of a protein corona-based brain-targeted drug delivery system. More crucially, we utilized the unfavorable side of the protein corona and converted it into an advantage to achieve brain-targeted drug delivery. Graphical Abstract

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“…The various Aβ42 peptides were treated as previously described, with some modifications. 31 Briefly, 1 mg Aβ peptides were combined with HFIP, vortexed for 2 min and incubated overnight at 4 °C with gentle shaking. The Aβ solution was aliquoted and stored at −80 °C after being evaporated in an N 2 flow.…”

Section: Methodsmentioning

confidence: 99%

N-terminal Domain of Amyloid-β Impacts Fibrillation and Neurotoxicity

Shi

Liu

et al. 2022

ACS Omega

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Alzheimer’s disease is characterized by the presence of distinct amyloid-β peptide (Aβ) assemblies with diverse sizes, shapes, and toxicity. However, the primary determinants of Aβ aggregation and neurotoxicity remain unknown. Here, the N-terminal amino acid residues of Aβ42 that distinguished between humans and rats were substituted. The effects of these modifications on the ability of Aβ to aggregate and its neurotoxicity were investigated using biochemical, biophysical, and cellular techniques. The Aβ-derived diffusible ligand, protofibrils, and fibrils formed by the N-terminal mutational peptides, including Aβ42(R5G), Aβ42(Y10F), and rat Aβ42, were indistinguishable by conventional techniques such as size-exclusion chromatography, negative-staining transmission electron microscopy and silver staining, whereas the amyloid fibrillation detected by thioflavin T assay was greatly inhibited in vitro. Using circular dichroism spectroscopy, we discovered that both Aβ42 and Aβ42(Y10F) generated protofibrils and fibrils with a high proportion of parallel β-sheet structures. Furthermore, protofibrils formed by other mutant Aβ peptides and N-terminally shortened peptides were incapable of inducing neuronal death, with the exception of Aβ42 and Aβ42(Y10F). Our findings indicate that the N-terminus of Aβ is important for its fibrillation and neurotoxicity.

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Endocytosis Is a Key Mode of Interaction between Extracellular β-Amyloid and the Cell Membrane

Cited by 11 publications

References 65 publications

Internalized Amyloid-β (1-42) Peptide Inhibits the Store-Operated Calcium Entry in HT-22 Cells

Internalized Amyloid-β (1-42) Peptide Inhibits the Store-Operated Calcium Entry in HT-22 Cells

Novel brain-targeted nanomicelles for anti-glioma therapy mediated by the ApoE-enriched protein corona in vivo

N-terminal Domain of Amyloid-β Impacts Fibrillation and Neurotoxicity

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