ArticleAnnals of neurology2019
Neuronal apolipoprotein E4 increases cell death and phosphorylated tau release in alzheimer disease.
Article in Annals of neurology, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 78 papers, 1 of them a synthesis that pooled it.
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Who cites it
78 citing papers in PubMed, 1 synthesis or guideline pooled it, 143 citations in OpenAlex.
- Advances in gait research related to Alzheimer's disease.Frontiers in neurology · 2025Pooled it
- Ca:Mg Ratio, APOE Cytosine Modifications, and Cognitive Function: Results from a Randomized Trial.Journal of Alzheimer's disease : JAD · 2020Trial
- ApoE4 as a Therapeutic Target in Epilepsy: From Pathogenic Mechanisms to Precision Medicine.CNS neuroscience & therapeutics · 2026Review
- Review
- The Role of Lipoprotein and Gut Microbiome in Alzheimer's Disease: A Review of Novel Findings and Potential Applications.Current Alzheimer research · 2026Review
- An overview of gene and cell therapy approaches for Alzheimer's disease.Metabolic brain disease · 2025Review
- APOE Lipoprotein Particles: Pathophysiology, Therapy, and the Crosstalk in Alzheimer's Disease and Cardiovascular Disease.Molecular neurobiology · 2025Review
- Deciphering the role of APOE in cerebral amyloid angiopathy: from genetic insights to therapeutic horizons.Annals of medicine · 2025Review
- The Synergistic Role of ApoE4 and GSK3β in Alzheimer's Disease: Pathological Mechanisms and Therapeutic Implications.Molecular neurobiology · 2025Review
- Advances of therapeutic strategies for Alzheimer's disease.Journal of neurology · 2025Review
- CRISPR in Neurodegenerative Diseases Treatment: An Alternative Approach to Current Therapies.Genes · 2025Review
- The multifaceted roles of apolipoprotein E4 in Alzheimer's disease pathology and potential therapeutic strategies.Cell death discovery · 2025Review
- Variable and interactive effects of Sex, APOE ε4 and TREM2 on the deposition of tau in entorhinal and neocortical regions.Nature communications · 2025Article
- PGRN as an emerging regulator of lipid metabolism in neurodegenerative diseases.Communications biology · 2025Review
- Inhibition of Bone Morphogenetic Protein Signaling Prevents Tau Pathology in iPSC Derived Neurons and PS19 Mice.Annals of neurology · 2025Article
- Could Blood Transfusion Increase the Risk of Alzheimer's Disease? A Narrative Review.Healthcare (Basel, Switzerland) · 2025Review
- From Genetics to Neuroinflammation: The Impact of ApoE4 on Microglial Function in Alzheimer's Disease.Cells · 2025Review
- Optimized prime editing of the Alzheimer's disease-associated APOE4 mutation.Stem cell reports · 2025Article
- Microglia depletion reduces human neuronal APOE4-related pathologies in a chimeric Alzheimer's disease model.Cell stem cell · 2025Article
- Multi-functional role of apolipoprotein E in neurodegenerative diseases.Frontiers in aging neuroscience · 2025Review
18 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
4 authors at 1 institution in 2 countries.
Funding
Abstract
objectiveThe apolipoprotein E (APOE) E4 isoform is the strongest genetic risk factor for sporadic Alzheimer disease (AD). Although APOE is predominantly expressed by astrocytes in the central nervous system, neuronal expression of APOE is of increasing interest in age-related cognitive impairment, neurological injury, and neurodegeneration. Here, we show that endogenous expression of E4 in stem-cell-derived neurons predisposes them to injury and promotes the release of phosphorylated tau.
methodsInduced pluripotent stem cells from 2 unrelated AD patients carrying the E4 allele were corrected to the E3/E3 genotype with the CRISPR/Cas9 system and differentiated into pure cultures of forebrain excitatory neurons without contamination from other cells types.
resultsCompared to unedited E4 neurons, E3 neurons were less susceptible to ionomycin-induced cytotoxicity. Biochemically, E4 cells exhibited increased tau phosphorylation and ERK1/2 phosphoactivation. Moreover, E4 neurons released increased amounts of phosphorylated tau extracellularly in an isoform-dependent manner by a heparin sulfate proteoglycan-dependent mechanism.
interpretationOur results demonstrate that endogenous expression of E4 by stem-cell-derived forebrain excitatory neurons predisposes neurons to calcium dysregulation and ultimately cell death. This change is associated with increased cellular tau phosphorylation and markedly enhanced release of phosphorylated tau. Importantly, these effects are independent of glial APOE. These findings suggest that E4 accelerates spreading of tau pathology and neuron death in part by neuron-specific, glia-independent mechanisms. Ann Neurol 2019;85:726-739.
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