ArticleJournal of Alzheimer's disease : JAD2017
Apolipoprotein E4 Elicits Lysosomal Cathepsin D Release, Decreased Thioredoxin-1 Levels, and Apoptosis.
Article in Journal of Alzheimer's disease : JAD, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.
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Who cites it
26 citing papers in PubMed, 41 citations in OpenAlex.
- Organelle stress in NLRP3 inflammasome: a central mediator of neurodegenerative diseases.Molecular neurodegeneration · 2026Review
- Lysosomal dysfunction in diabetes and diabetic complications.Frontiers in endocrinology · 2026Review
- Targeting ALDH16A1 mediated thioredoxin lysosomal degradation to enhance ferroptosis susceptibility in SMARCA4-deficient NSCLC.Nature communications · 2025Article
- The multifaceted roles of apolipoprotein E4 in Alzheimer's disease pathology and potential therapeutic strategies.Cell death discovery · 2025Review
- Inflammation-induced lysosomal dysfunction in human iPSC-derived microglia is exacerbated by APOE 4/4 genotype.Journal of neuroinflammation · 2025Article
- Plasma Homocysteine Levels and Intracerebral Hemorrhage: A Mendelian Randomization Analysis.Cureus · 2025Article
- Lysosomal acidification impairment in astrocyte-mediated neuroinflammation.Journal of neuroinflammation · 2025Review
- Age- and ApoE Genotype-Dependent Transcriptomic Responses to OInternational journal of molecular sciences · 2025Article
- Thioredoxin-1 decreases alpha-synuclein induced by MPTP through promoting autophagy-lysosome pathway.Cell death discovery · 2024Article
- Endosomal Acid-Base Homeostasis in Neurodegenerative Diseases.Reviews of physiology, biochemistry and pharmacology · 2023Article
- A multi-hit hypothesis for an APOE4-dependent pathophysiological state.The European journal of neuroscience · 2022Review
- Pharmacological modulation of autophagy for Alzheimer's disease therapy: Opportunities and obstacles.Acta pharmaceutica Sinica. B · 2022Review
- Isoform-dependent lysosomal degradation and internalization of apolipoprotein E requires autophagy proteins.Journal of cell science · 2022Article
- A Review of ApoE4 Interference Targeting Mitophagy Molecular Pathways for Alzheimer's Disease.Frontiers in aging neuroscience · 2022Review
- Isoform-Specific Effects of Apolipoprotein E on Hydrogen Peroxide-Induced Apoptosis in Human Induced Pluripotent Stem Cell (iPSC)-Derived Cortical Neurons.International journal of molecular sciences · 2021Article
- HDL Proteome and Alzheimer's Disease: Evidence of a Link.Antioxidants (Basel, Switzerland) · 2020Review
- Apolipoprotein E and oxidative stress in brain with relevance to Alzheimer's disease.Neurobiology of disease · 2020Review
- STVNa Attenuates Isoproterenol-Induced Cardiac Hypertrophy Response through the HDAC4 and Prdx2/ROS/Trx1 Pathways.International journal of molecular sciences · 2020Article
- Cyclic ONeurobiology of aging · 2019Article
- Molecular Mechanisms and Genetics of Oxidative Stress in Alzheimer's Disease.Journal of Alzheimer's disease : JAD · 2019Review
Corrections and comments
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Authors and funding
9 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The major genetic risk factor for Alzheimer's disease (AD), apolipoprotein E4 (ApoE4), has been suggested to have detrimental effects on neurons, including direct toxicity via apoptosis. Thioredoxin-1 (Trx1) is an endogenous antioxidant protein important for redox regulation and participates in the regulation of apoptosis through the inhibition of apoptosis signal-regulating kinase-1 (Ask-1). In this study, we have investigated the effects of ApoE on Trx1 in the brain. Our results showed that the protein levels of Trx1 were reduced in the hippocampus of ApoE4 targeted replacement (TR) mice compared to ApoE3 TR mice. The reduction was also seen in vitro after treatment of both human primary cortical neurons and neuroblastoma cells with human recombinant ApoE4 (rApoE4). Furthermore, ApoE4 caused a disruption of lysosomal integrity and a shift in the localization of Cathepsin D, an enzyme known to degrade Trx1. ApoE4 treatment induced in addition apoptosis through translocation of Death-domain associated protein-6 (Daxx) from the nucleus to the cytosol, suggesting an activation of the Ask-1 pathway. This toxicity was prevented by overexpression of Trx1 and other endogenous Ask-1 inhibitors. Our data suggests that down-regulation of Trx1 is involved in the toxicity caused by ApoE4. An activated ASK-1 pathway might indeed make cells more vulnerable to other insults such as amyloid-β, which could partially explain the mechanism behind the strongest genetic risk factor for AD.
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