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Cited by 19Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

Lipid Peroxidation Induced ApoE Receptor-Ligand Disruption as a Unifying Hypothesis Underlying Sporadic Alzheimer’s Disease in Humans

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Ramsden, Christopher E., Keyes, Gregory S., Calzada, Elizabeth, Horowitz, Mark S., Zamora, Daisy, Jahanipour, Jahandar, Sedlock, Andrea, Indig, Fred E. +3 more·2022·Journal of Alzheimer's Disease
DOI 10.3233/jad-220071PMC PMC9268955

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Abstract

Background: Sporadic 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. Objective: We 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. Methods: In 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. Results: ApoE 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. Conclusion: Results 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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Cited by

Sorted by citations

Authors
Ramsden, C. E., Keyes, G. S., Calzada, E., Horowitz, M. S., Zamora, D., Jahanipour, J., Sedlock, A., Indig, F. E., Moaddel, R., Kapogiannis, D., & Maric, D.
Affiliations
  • National Institutes of Health (US)
  • University of North Carolina at Chapel Hill (US)
Corresponding author
Ramsden, Christopher E.
ORCID
Venue
Journal of Alzheimer's Disease
Publisher
SAGE Publications
Published
2022-05-31
Volume
87
Issue
3
Pages
1251-1290
ISSN
  • 1387-2877 (ISSN-L)
  • 1875-8908
DOI
10.3233/jad-220071
PMC
PMC9268955
OpenAlex
W4224235666
Cited by
19
References
20
Citations by year
2026: 3 · 2025: 5 · 2024: 5 · 2023: 5 · 2022: 1
FWCI
2.48
Type
journal article
Language
en
Open access
Locations
  • Journal of Alzheimer s Disease (publishedVersion)
  • medRxiv (acceptedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institutes of Health
  • National Institute on Aging (P30AG019610, ZIAAG000456, ZIAAG000453)
  • National Institute of Neurological Disorders and Stroke (U24NS072026)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
sporadic Alzheimer's disease, lipid peroxidation
MeSH terms
Reelin Protein, Aldehydes, Alzheimer Disease, Apolipoproteins E, Humans, Ligands, Nerve Tissue Proteins, Receptors, LDL, Serine Endopeptidases, Lipid Peroxidation, Cell Adhesion Molecules, Neuronal, Extracellular Matrix Proteins, LDL-Receptor Related Proteins, Low Density Lipoprotein Receptor-Related Protein-1, Plaque, Amyloid

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