Crosstalk between Lipid Rafts and Aging: New Frontiers for Delaying Aging

Zhang, Shuo; Zhu, Neng; Gu, Jingmin; Li, Hongfang; Qiu, Yun; Liao, Duan-Fang; Li, Qin

doi:10.14336/ad.2022.0116

Cited by 9 publications

(10 citation statements)

References 161 publications

(172 reference statements)

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“…It is important to note that the cellular system which allows the formation and detection of amyloid pores is a model of aged cells, used between the 20th and the 25th passage in culture. Cells freshly thawed after storage in liquid nitrogen are not permissive for the formation of amyloid pores, probably due to changes in the lipid composition upon membrane aging [ 47 , 48 , 49 , 50 ]. Such phenomena have been reported for several cell types used as models for studies of pathological processes [ 51 , 52 , 53 ].…”

Section: Discussionmentioning

confidence: 99%

AmyP53 Prevents the Formation of Neurotoxic β-Amyloid Oligomers through an Unprecedent Mechanism of Interaction with Gangliosides: Insights for Alzheimer’s Disease Therapy

Azzaz

Chahinian

Yahi

et al. 2023

IJMS

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A broad range of data identify Ca2+-permeable amyloid pores as the most neurotoxic species of Alzheimer’s β-amyloid peptide (Aβ1–42). Following the failures of clinical trials targeting amyloid plaques by immunotherapy, a consensus is gradually emerging to change the paradigm, the strategy, and the target to cure Alzheimer’s disease. In this context, the therapeutic peptide AmyP53 was designed to prevent amyloid pore formation driven by lipid raft microdomains of the plasma membrane. Here, we show that AmyP53 outcompetes Aβ1–42 binding to lipid rafts through a unique mode of interaction with gangliosides. Using a combination of cellular, physicochemical, and in silico approaches, we unraveled the mechanism of action of AmyP53 at the atomic, molecular, and cellular levels. Molecular dynamics simulations (MDS) indicated that AmyP53 rapidly adapts its conformation to gangliosides for an optimal interaction at the periphery of a lipid raft, where amyloid pore formation occurs. Hence, we define it as an adaptive peptide. Our results describe for the first time the kinetics of AmyP53 interaction with lipid raft gangliosides at the atomic level. Physicochemical studies and in silico simulations indicated that Aβ1–42 cannot interact with lipid rafts in presence of AmyP53. These data demonstrated that AmyP53 prevents amyloid pore formation and cellular Ca2+ entry by competitive inhibition of Aβ1–42 binding to lipid raft gangliosides. The molecular details of AmyP53 action revealed an unprecedent mechanism of interaction with lipid rafts, offering innovative therapeutic opportunities for lipid raft and ganglioside-associated diseases, including Alzheimer’s, Parkinson’s, and related proteinopathies.

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Section: Discussionmentioning

confidence: 99%

AmyP53 Prevents the Formation of Neurotoxic β-Amyloid Oligomers through an Unprecedent Mechanism of Interaction with Gangliosides: Insights for Alzheimer’s Disease Therapy

Azzaz

Chahinian

Yahi

et al. 2023

IJMS

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“…So, the cholesterol content of the neutrophil membrane increases, while membrane phospholipid levels do not change. Moreover, lipid raft distribution is disorganized with aging, which reduces lipid raft accumulation and disrupts downstream signaling events in aged neutrophils ( Fulop et al, 2004 ; Zhang et al, 2022 ). Thus, signaling through receptors such as granulocyte macrophage-colony stimulating factor (GM-CSF) or formyl-methionyl-leucyl-phenylalanine (fMLP) receptor, activation of the Janus kinase/signal transducer and activator of transcription (JAK/STAT), extracellular signal-related kinases 1 and 2 (ERK1/2), PLCγ/protein kinase C (PKC) and phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) pathways will be reduced.…”

Section: Metabolic Alterations In Innate Immune Cellsmentioning

confidence: 99%

Alterations in metabolic pathways: a bridge between aging and weaker innate immune response

Saleh,

Mirzazadeh,

Mirzaei

et al. 2024

Front. Aging

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Aging is a time-dependent progressive physiological process, which results in impaired immune system function. Age-related changes in immune function increase the susceptibility to many diseases such as infections, autoimmune diseases, and cancer. Different metabolic pathways including glycolysis, tricarboxylic acid cycle, amino acid metabolism, pentose phosphate pathway, fatty acid oxidation and fatty acid synthesis regulate the development, differentiation, and response of adaptive and innate immune cells. During aging all these pathways change in the immune cells. In addition to the changes in metabolic pathways, the function and structure of mitochondria also have changed in the immune cells. Thereby, we will review changes in the metabolism of different innate immune cells during the aging process.

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“…Meanwhile, SASP facilitates CSCs by providing chemokines and inflammatory cytokines (such as IL-1β, IL-8, and CXCR1) [ 179 , 180 ]. The recently published review by our group revealed that lipid rafts and their component protein are integral parts of cellular senescence [ 154 ]. For example, caveolin-1 induces senescence by activating P53 though affecting Mdm2 (mouse double minute 2 homolog), PP2A-C (protein phosphatase 2A-C subunit), Sirt1, TrxR1 (thioredoxin reductase 1), Nrf2 (nuclear factor erythroid-2-related factor-2), and EGFR (epidermal growth factor receptor) [ 154 ].…”

Section: Csc Niche and Lipid Raftmentioning

confidence: 99%

“…The recently published review by our group revealed that lipid rafts and their component protein are integral parts of cellular senescence [ 154 ]. For example, caveolin-1 induces senescence by activating P53 though affecting Mdm2 (mouse double minute 2 homolog), PP2A-C (protein phosphatase 2A-C subunit), Sirt1, TrxR1 (thioredoxin reductase 1), Nrf2 (nuclear factor erythroid-2-related factor-2), and EGFR (epidermal growth factor receptor) [ 154 ]. It is feasible to manipulate lipid rafts to suppress cellular senescence and minimize the effects of SASP on the CSC niche.…”

Section: Csc Niche and Lipid Raftmentioning

confidence: 99%

The lipid rafts in cancer stem cell: a target to eradicate cancer

Zhang

Zhu

et al. 2022

Stem Cell Res Ther

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Cancer stem cells (CSCs) are a subpopulation of cancer cells with stem cell properties that sustain cancers, which may be responsible for cancer metastasis or recurrence. Lipid rafts are cholesterol- and sphingolipid-enriched microdomains in the plasma membrane that mediate various intracellular signaling. The occurrence and progression of cancer are closely related to lipid rafts. Emerging evidence indicates that lipid raft levels are significantly enriched in CSCs compared to cancer cells and that most CSC markers such as CD24, CD44, and CD133 are located in lipid rafts. Furthermore, lipid rafts play an essential role in CSCs, specifically in CSC self-renewal, epithelial-mesenchymal transition, drug resistance, and CSC niche. Therefore, lipid rafts are critical regulatory platforms for CSCs and promising therapeutic targets for cancer therapy.

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Crosstalk between Lipid Rafts and Aging: New Frontiers for Delaying Aging

Cited by 9 publications

References 161 publications

AmyP53 Prevents the Formation of Neurotoxic β-Amyloid Oligomers through an Unprecedent Mechanism of Interaction with Gangliosides: Insights for Alzheimer’s Disease Therapy

AmyP53 Prevents the Formation of Neurotoxic β-Amyloid Oligomers through an Unprecedent Mechanism of Interaction with Gangliosides: Insights for Alzheimer’s Disease Therapy

Alterations in metabolic pathways: a bridge between aging and weaker innate immune response

The lipid rafts in cancer stem cell: a target to eradicate cancer

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