Lipid Peroxidation Induced ApoE Receptor-Ligand Disruption as a Unifying Hypothesis Underlying Sporadic Alzheimer's Disease in Humans.
Aldehydes
Alzheimer Disease
/ genetics
Apolipoproteins E
/ genetics
Cell Adhesion Molecules, Neuronal
/ metabolism
Extracellular Matrix Proteins
/ metabolism
Humans
LDL-Receptor Related Proteins
/ metabolism
Ligands
Lipid Peroxidation
Low Density Lipoprotein Receptor-Related Protein-1
/ metabolism
Nerve Tissue Proteins
/ metabolism
Plaque, Amyloid
Receptors, LDL
/ metabolism
Reelin Protein
Serine Endopeptidases
/ metabolism
Alzheimer’s disease
ApoE
ApoER2
Thr19-phosphorylated PSD95
disabled homolog 1
lipid peroxidation
perforant path
polyunsaturated
pyrrole crosslink
reelin
Journal
Journal of Alzheimer's disease : JAD
ISSN: 1875-8908
Titre abrégé: J Alzheimers Dis
Pays: Netherlands
ID NLM: 9814863
Informations de publication
Date de publication:
2022
2022
Historique:
pubmed:
26
4
2022
medline:
9
6
2022
entrez:
25
4
2022
Statut:
ppublish
Résumé
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. 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. 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. 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. 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.
Sections du résumé
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.
Identifiants
pubmed: 35466940
pii: JAD220071
doi: 10.3233/JAD-220071
pmc: PMC9268955
mid: NIHMS1816711
doi:
Substances chimiques
Aldehydes
0
Apolipoproteins E
0
Cell Adhesion Molecules, Neuronal
0
Extracellular Matrix Proteins
0
LDL-Receptor Related Proteins
0
Ligands
0
Low Density Lipoprotein Receptor-Related Protein-1
0
Nerve Tissue Proteins
0
Receptors, LDL
0
Reelin Protein
0
Serine Endopeptidases
EC 3.4.21.-
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Research Support, N.I.H., Intramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
1251-1290Subventions
Organisme : NIA NIH HHS
ID : P30 AG019610
Pays : United States
Organisme : NINDS NIH HHS
ID : U24 NS072026
Pays : United States
Organisme : Intramural NIH HHS
ID : ZIA AG000453
Pays : United States
Organisme : Intramural NIH HHS
ID : ZIA AG000456
Pays : United States
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