ArticleJournal of Alzheimer's disease : JAD2022
Lipid Peroxidation Induced ApoE Receptor-Ligand Disruption as a Unifying Hypothesis Underlying Sporadic Alzheimer's Disease in Humans.
Article in Journal of Alzheimer's disease : JAD, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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Who cites it
12 citing papers in PubMed, 19 citations in OpenAlex.
- 1,8-Cineole Alleviates PA-Induced Lipid Accumulation, Oxidative Stress, and Inflammation via the TLR4/MyD88/NF-κB Signaling Pathway.Molecules (Basel, Switzerland) · 2026Article
- Ser423-phosphorylated MECP2 (MECP2-pS423) accumulates in human brain, cerebrospinal fluid and serum in sporadic Alzheimer's disease.Acta neuropathologica · 2026Article
- HYPOTHESIS: Lipid-protecting disulfide bridges are the missing molecular link between ApoE4 and sporadic Alzheimer's disease in humans.Prostaglandins, leukotrienes, and essential fatty acids · 2025Article
- Efficient removal of naturally-occurring lipofuscin autofluorescence in human nervous tissue using high-intensity white light.The journal of pain · 2025Article
- Article
- Short lifespan is one's fate, long lifespan is one's achievement: lessons from Daphnia.GeroScience · 2024Article
- Spatial Multi-Omics in Alzheimer's Disease: A Multi-Dimensional Approach to Understanding Pathology and Progression.Current issues in molecular biology · 2024Review
- The Inflammation-Induced Dysregulation of Reelin Homeostasis Hypothesis of Alzheimer's Disease.Journal of Alzheimer's disease : JAD · 2024Review
- ApoER2-Dab1 disruption as the origin of pTau-associated neurodegeneration in sporadic Alzheimer's disease.Acta neuropathologica communications · 2023Article
- Reelin Plasma Levels Identify Cognitive Decline in Alcohol Use Disorder Patients During Early Abstinence: The Influence of APOE4 Expression.The international journal of neuropsychopharmacology · 2023Article
- Lipofuscin, amyloids, and lipid peroxidation as potential markers of aging in Daphnia.Biogerontology · 2023Article
- Flying under the radar: CDH2 (N-cadherin), an important hub molecule in neurodevelopmental and neurodegenerative diseases.Frontiers in neuroscience · 2022Review
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Authors and funding
11 authors at 2 institutions in 1 country.
Funding
Abstract
backgroundSporadic Alzheimer's disease (sAD) lacks a unifying hypothesis that can account for the lipid peroxidation observed early in the disease, enrichment of ApoE in the core of neuritic plaques, hallmark plaques and tangles, and selective vulnerability of entorhinal-hippocampal structures.
objectiveWe hypothesized that 1) high expression of ApoER2 (receptor for ApoE and Reelin) helps explain this anatomical vulnerability; 2) lipid peroxidation of ApoE and ApoER2 contributes to sAD pathogenesis, by disrupting neuronal ApoE delivery and Reelin-ApoER2-Dab1 signaling cascades.
methodsIn vitro biochemical experiments; Single-marker and multiplex fluorescence-immunohistochemistry (IHC) in postmortem specimens from 26 individuals who died cognitively normal, with mild cognitive impairment or with sAD.
resultsApoE and ApoER2 peptides and proteins were susceptible to attack by reactive lipid aldehydes, generating lipid-protein adducts and crosslinked ApoE-ApoER2 complexes. Using in situ hybridization alongside IHC, we observed that: 1) ApoER2 is strongly expressed in terminal zones of the entorhinal-hippocampal 'perforant path' projections that underlie memory; 2) ApoE, lipid aldehyde-modified ApoE, Reelin, ApoER2, and the downstream Reelin-ApoER2 cascade components Dab1 and Thr19-phosphorylated PSD95 accumulated in the vicinity of neuritic plaques in perforant path terminal zones in sAD cases; 3) several ApoE/Reelin-ApoER2-Dab1 pathway markers were higher in sAD cases and positively correlated with histological progression and cognitive deficits.
conclusionResults demonstrate derangements in multiple ApoE/Reelin-ApoER2-Dab1 axis components in perforant path terminal zones in sAD and provide proof-of-concept that ApoE and ApoER2 are vulnerable to aldehyde-induced adduction and crosslinking. Findings provide the foundation for a unifying hypothesis implicating lipid peroxidation of ApoE and ApoE receptors in sAD.
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