Lipidation of apolipoprotein E influences its isoform-specific interaction with Alzheimer's amyloid β peptides

Takahiko Tokuda, Miguel Calero, Etsuro Matsubara, Ruben Vidal, Asok Kumar, Bruno Permanne, Berislav Zlokovic, Jonathan D. Smith, Mary Jo Ladu, Agueda Rostagno, Blas Frangione, Jorge Ghiso

Research output: Contribution to journalArticle

175 Citations (Scopus)

Abstract

The inheritance of the apolipoprotein E (apoE) ε4 allele is a prevailing risk factor for sporadic and familial Alzheimer's disease (AD). ApoE isoforms bind directly to Alzheimer's amyloid β (Aβ) peptides both in vitro and in vivo. Recent studies suggest that association of apoE with lipids may modulate its interaction with Aβ. We examined the binding of lipid-associated and delipidated apoE3 and apoE4 isoforms to Aβ utilizing a solid-phase binding assay and estimated the dissociation constants for the interaction of various apoE and Aβ species. Using native apoE isoforms from stably transfected RAW 264 and human embryonic kidney 293 cells, apoE3 had greater affinity than apoE4 for both Aβ1-40 and Aβ1-42. Delipidation of apoE decreased its affinity for Aβ peptides by 5-10-fold and abolished the isoform-specificity. Conversely, incorporation of apoE isoforms produced by baculovirus-infected Sf9 cells into reconstituted human high-density-lipoprotein lipoparticles restored the affinity values for Aβ peptides and resulted in preferential binding of apoE3. The data demonstrate that native lipid-associated apoE3 binds to Aβ peptides with 2-3-fold higher affinity than lipid-associated apoE4. Since the isoforms' binding efficiency correlate inversely with the risk of developing late-onset AD, the results suggest a possible involvement of apoE3 in the clearance or routing out of Aβ from the central nervous system as one of the mechanisms underlying the pathology of the disease.

Original languageEnglish (US)
Pages (from-to)359-365
Number of pages7
JournalBiochemical Journal
Volume348
Issue number2
DOIs
StatePublished - Jun 1 2000
Externally publishedYes

Fingerprint

Apolipoprotein E3
Apolipoproteins E
Amyloid
Apolipoprotein E4
Protein Isoforms
Peptides
Lipids
Alzheimer Disease
Dissociative Disorders
Apolipoproteins A
Sf9 Cells
Baculoviridae
Neurology
Pathology
HDL Lipoproteins
Assays
Central Nervous System
Alleles
Association reactions
Kidney

Keywords

  • ApoE isoform
  • Dissociation constant
  • HDL
  • Lipid

ASJC Scopus subject areas

  • Biochemistry

Cite this

Lipidation of apolipoprotein E influences its isoform-specific interaction with Alzheimer's amyloid β peptides. / Tokuda, Takahiko; Calero, Miguel; Matsubara, Etsuro; Vidal, Ruben; Kumar, Asok; Permanne, Bruno; Zlokovic, Berislav; Smith, Jonathan D.; Ladu, Mary Jo; Rostagno, Agueda; Frangione, Blas; Ghiso, Jorge.

In: Biochemical Journal, Vol. 348, No. 2, 01.06.2000, p. 359-365.

Research output: Contribution to journalArticle

Tokuda, T, Calero, M, Matsubara, E, Vidal, R, Kumar, A, Permanne, B, Zlokovic, B, Smith, JD, Ladu, MJ, Rostagno, A, Frangione, B & Ghiso, J 2000, 'Lipidation of apolipoprotein E influences its isoform-specific interaction with Alzheimer's amyloid β peptides', Biochemical Journal, vol. 348, no. 2, pp. 359-365. https://doi.org/10.1042/0264-6021:3480359
Tokuda, Takahiko ; Calero, Miguel ; Matsubara, Etsuro ; Vidal, Ruben ; Kumar, Asok ; Permanne, Bruno ; Zlokovic, Berislav ; Smith, Jonathan D. ; Ladu, Mary Jo ; Rostagno, Agueda ; Frangione, Blas ; Ghiso, Jorge. / Lipidation of apolipoprotein E influences its isoform-specific interaction with Alzheimer's amyloid β peptides. In: Biochemical Journal. 2000 ; Vol. 348, No. 2. pp. 359-365.
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