Membrane Aging as the Real Culprit of Alzheimer’s Disease: Modification of a Hypothesis

Yu, Qiujian; Zhong, Chunjiu

doi:10.1007/s12264-017-0192-4

Cited by 12 publications

(6 citation statements)

References 156 publications

(151 reference statements)

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“…Such a decrease was already shown in a SOD1-mouse model of ALS and could be related to the neuronal loss observed in these animals [36]. One possible hypothesis is that TDP-43 alters the composition of the cellular membrane and renders it more permeable (following the membrane hypothesis of aging [37]). The increase in the permeability of the cell membrane induced by TDP-43 can also explain the increase in PI staining at TDP-43 4 µg.…”

Section: Alteration Of Cell Metabolome Induced By Tdp-43 Overexpressionmentioning

confidence: 68%

TDP-43-Mediated Toxicity in HEK293T Cells: A Fast and Reproducible Protocol To Be Employed in the Search of New Therapeutic Options against Amyotrophic Lateral Sclerosis

Lanznaster

Bourgeais

Bruno

et al. 2019

Cells

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Cytoplasmic TDP-43 aggregates are a hallmark of amyotrophic lateral sclerosis (ALS). Today, only two drugs are available for ALS treatment, and their modest effect prompts researchers to search for new therapeutic options. TDP-43 represents one of the most promising targets for therapeutic intervention, but reliable and reproducible in vitro protocols for TDP-43-mediated toxicity are lacking. Here, we used HEK293T cells transfected with increasing concentrations of TDP-43-expressing plasmid to evaluate different parameters of toxicity and alterations in cellular metabolism. Overexpression of TDP-43 induced aggregates occurrence followed by the detection of 25-and 35-kDa forms of TDP-43. TDP-43 overexpression decreased cell viability and increased cells arrested at G2/M phase and nuclear fragmentation. Analysis of the energetic metabolism showed a tendency to decrease oxidative phosphorylation and increase glycolysis, but no statistical differences were observed. Metabolomics revealed alterations in different metabolites (mainly sphingolipids and glycerophospholipids) in cells overexpressing TDP-43. Our data reveal the main role of TDP-43 aggregation in cellular death and highlight novel insight into the mechanism of cellular toxicity induced by TDP-43. Here, we provide a simple, sensitive, and reliable protocol in a human-derived cell line to be used in high-throughput screenings of potential therapeutic molecules for ALS treatment.

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Section: Alteration Of Cell Metabolome Induced By Tdp-43 Overexpressionmentioning

confidence: 68%

TDP-43-Mediated Toxicity in HEK293T Cells: A Fast and Reproducible Protocol To Be Employed in the Search of New Therapeutic Options against Amyotrophic Lateral Sclerosis

Lanznaster

Bourgeais

Bruno

et al. 2019

Cells

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“…AD is the leading worldwide cause of dementia among the population over 65 years of age. People affected by this pathology suffer a progressive loss of memory and a decrease in their cognitive capabilities in the earliest stages of the disease, which develops into dementia in its most advanced stages [236]. This section focuses on the brain lipid alterations related to neurodegenerative diseases and to AD in particular.…”

Section: Lipids In the Pathophysiology Of Neurodegenerative Diseasesmentioning

confidence: 99%

Lipids in Pathophysiology and Development of the Membrane Lipid Therapy: New Bioactive Lipids

et al. 2021

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Membranes are mainly composed of a lipid bilayer and proteins, constituting a checkpoint for the entry and passage of signals and other molecules. Their composition can be modulated by diet, pathophysiological processes, and nutritional/pharmaceutical interventions. In addition to their use as an energy source, lipids have important structural and functional roles, e.g., fatty acyl moieties in phospholipids have distinct impacts on human health depending on their saturation, carbon length, and isometry. These and other membrane lipids have quite specific effects on the lipid bilayer structure, which regulates the interaction with signaling proteins. Alterations to lipids have been associated with important diseases, and, consequently, normalization of these alterations or regulatory interventions that control membrane lipid composition have therapeutic potential. This approach, termed membrane lipid therapy or membrane lipid replacement, has emerged as a novel technology platform for nutraceutical interventions and drug discovery. Several clinical trials and therapeutic products have validated this technology based on the understanding of membrane structure and function. The present review analyzes the molecular basis of this innovative approach, describing how membrane lipid composition and structure affects protein-lipid interactions, cell signaling, disease, and therapy (e.g., fatigue and cardiovascular, neurodegenerative, tumor, infectious diseases).

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“…Alzheimer's disease (AD) is the leading cause of dementia. Over 90% of AD cases have a late-onset, occurring in individuals older than 65 [1]. AD is characterized by gradual memory loss associated with progressive brain atrophy.…”

Section: Introductionmentioning

confidence: 99%

A Bioinformatics Perspective on the Dysregulation of Ferroptosis and Ferroptosis-related Immune Cell Infiltration in Alzheimer's Disease

Zhang¹,

Fang²,

Tang³

et al. 2022

Int. J. Med. Sci.

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Alzheimer's disease (AD) is the most prevalent dementia worldwide, but its pathophysiology and molecular events remain unknown. Herein, we first analyzed the differential expression pattern of patients' AD hippocampus through gene expression array data from the GEO database. Notch2nl, TGFB1I1, and LTF were up-regulated in AD patients, while ARPC1A, CHGB, and MPV17 down-regulated. Second, dysregulation of ferroptosis related genes was demonstrated from our data: PCBP2 and FTL significantly up-significant in AD hippocampus, while VDAC2, LPCAT3, GSS, ACSL4, and ACSL6 significantly down-regulated. The protein-protein interactions (PPI) network revealed that FTL was involved in iron metabolism and utilization, while ACSL4 and ACSL6 were involved in a polyunsaturated fatty acids metabolism network. Gene correlation analysis on differential expressed genes (DEGs) indicated that ferroptosis regulates a series of biological processes and pathways related to AD pathogenesis. Third, ferroptosis-related DEGs regulated the immune cell infiltration pattern in the AD hippocampus, characterized by decreased memory B cells, increased memory resting CD4 + T cells, memory activated CD4 + T cells, and resting NK cells. The altered expression of ferroptosis-related DEGs affected the infiltration of specific immune cell types. The model constructed by the seven ferroptosis-related differential genes may accurately predict the outcome of AD occurrence. Finally, qPCR validation on these ferroptosis-related DEGs in APPswe/PSEN1dE9 mice confirmed the dysregulated expression of Pcbp2, FTL, GSS, and ACSL4 in the AD hippocampus and forebrain. In conclusion, our results supported the conception that the AD brain revealed dysregulated ferroptosis and immune cell infiltration.

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Membrane Aging as the Real Culprit of Alzheimer’s Disease: Modification of a Hypothesis

Cited by 12 publications

References 156 publications

TDP-43-Mediated Toxicity in HEK293T Cells: A Fast and Reproducible Protocol To Be Employed in the Search of New Therapeutic Options against Amyotrophic Lateral Sclerosis

TDP-43-Mediated Toxicity in HEK293T Cells: A Fast and Reproducible Protocol To Be Employed in the Search of New Therapeutic Options against Amyotrophic Lateral Sclerosis

Lipids in Pathophysiology and Development of the Membrane Lipid Therapy: New Bioactive Lipids

A Bioinformatics Perspective on the Dysregulation of Ferroptosis and Ferroptosis-related Immune Cell Infiltration in Alzheimer's Disease

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