ArticleThe Journal of biological chemistry2014
Molecular basis for increased risk for late-onset Alzheimer disease due to the naturally occurring L28P mutation in apolipoprotein E4.
Article in The Journal of biological chemistry, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers, 1 of them a synthesis that pooled it.
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Who cites it
18 citing papers in PubMed, 1 synthesis or guideline pooled it, 30 citations in OpenAlex.
- Investigation of the independent role of a rare APOE variant (L28P; APOE*4Pittsburgh) in late-onset Alzheimer disease.Neurobiology of aging · 2023Pooled it
- Alzheimer's Disease: From Pathogenesis to Emerging Therapeutic Targets.Journal of clinical medicine · 2026Review
- Impact of Apolipoprotein E Variants: A Review of Naturally Occurring Variants and Clinical Features.Journal of atherosclerosis and thrombosis · 2025Review
- A Comprehensive Review of the Genetics of Dyslipidemias and Risk of Atherosclerotic Cardiovascular Disease.Nutrients · 2025Review
- Spectrum and Prevalence of RareInternational journal of molecular sciences · 2024Article
- Current insights into apolipoprotein E and the immune response in Alzheimer's disease.Immunological reviews · 2024Review
- Human apolipoprotein E glycosylation and sialylation: from structure to function.Frontiers in molecular neuroscience · 2024Review
- Article
- Structural biology of cell surface receptors implicated in Alzheimer's disease.Biophysical reviews · 2022Review
- FH ALERT: efficacy of a novel approach to identify patients with familial hypercholesterolemia.Scientific reports · 2021Article
- APOE and dementia - resequencing and genotyping in 105,597 individuals.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2020Article
- The Genetic Variability ofGenes · 2019Review
- Thermodynamic destabilization and aggregation propensity as the mechanism behind the association of apoE3 mutants and lipoprotein glomerulopathy.Journal of lipid research · 2018Article
- Structural Biology Helps Interpret Variants of Uncertain Significance in Genes Causing Endocrine and Metabolic Disorders.Journal of the Endocrine Society · 2018Article
- Apolipoprotein E - A Multifunctional Protein with Implications in Various Pathologies as a Result of Its Structural Features.Computational and structural biotechnology journal · 2017Review
- The ability of apolipoprotein E fragments to promote intraneuronal accumulation of amyloid beta peptide 42 is both isoform and size-specific.Scientific reports · 2016Article
- Global molecular analysis and APOE mutations in a cohort of autosomal dominant hypercholesterolemia patients in France.Journal of lipid research · 2016Article
- Fluorescence study of domain structure and lipid interaction of human apolipoproteins E3 and E4.Biochimica et biophysica acta · 2014Article
Corrections and comments
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Authors and funding
6 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The apolipoprotein (apo) E4 isoform has consistently emerged as a susceptibility factor for late-onset Alzheimer disease (AD), although the exact mechanism is not clear. A rare apoE4 mutant, apoE4[L28P] Pittsburgh, burdens carriers with an added risk for late-onset AD and may be a useful tool for gaining insights into the role of apoE4 in disease pathogenesis. Toward this end, we evaluated the effect of the L28P mutation on the structural and functional properties of apoE4. ApoE4[L28P] was found to have significantly perturbed thermodynamic properties, to have reduced helical content, and to expose a larger portion of the hydrophobic surface to the solvent. Furthermore, this mutant is thermodynamically destabilized and more prone to proteolysis. When interacting with lipids, apoE4[L28P] formed populations of lipoprotein particles with structural defects. The structural perturbations brought about by the mutation were accompanied by aberrant functions associated with the pathogenesis of AD. Specifically, apoE4[L28P] promoted the cellular uptake of extracellular amyloid β peptide 42 (Aβ42) by human neuroblastoma SK-N-SH cells as well as by primary mouse neuronal cells and led to increased formation of intracellular reactive oxygen species that persisted for at least 24 h. Furthermore, lipoprotein particles containing apoE4[L28P] induced intracellular reactive oxygen species formation and reduced SK-N-SH cell viability. Overall, our findings suggest that the L28P mutation leads to significant structural and conformational perturbations in apoE4 and can induce functional defects associated with neuronal Aβ42 accumulation and oxidative stress. We propose that these structural and functional changes underlie the observed added risk for AD development in carriers of apoE4[L28P].
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