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

ABSTRACT: The inheritance of the apolipoprotein E (apoE) epsilon4 allele is a prevailing risk factor for sporadic and familial Alzheimer's disease (AD). ApoE isoforms bind directly to Alzheimer's amyloid beta (Abeta) peptides both in vitro and in vivo. Recent studies suggest that association of apoE with lipids may modulate its interaction with Abeta. We examined the binding of lipid-associated and delipidated apoE3 and apoE4 isoforms to Abeta utilizing a solid-phase binding assay and estimated the dissociation constants for the interaction of various apoE and Abeta species. Using native apoE isoforms from stably transfected RAW 264 and human embryonic kidney 293 cells, apoE3 had greater affinity than apoE4 for both Abeta1-40 and Abeta1-42. Delipidation of apoE decreased its affinity for Abeta 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 Abeta peptides and resulted in preferential binding of apoE3. The data demonstrate that native lipid-associated apoE3 binds to Abeta 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 Abeta from the central nervous system as one of the mechanisms underlying the pathology of the disease.

SUBMITTER: Tokuda T

PROVIDER: S-EPMC1221074 | biostudies-other | 2000 Jun

REPOSITORIES: biostudies-other

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Project description:Sporadic Alzheimer disease (AD) is caused in part by decreased clearance of the ?-amyloid (A?) peptide breakdown products. Lipid-depleted (LD) apolipoproteins are less effective at binding and clearing A?, and LD A? peptides are more toxic to neurons. However, not much is known about the lipid states of these proteins in human cerebrospinal fluid.To characterize the lipidation states of A? peptides and apolipoprotein E in the cerebrospinal fluid in adults with respect to cognitive diagnosis and APOE ?4 allele carrier status and after a dietary intervention.Randomized clinical trial.Veterans Affairs Medical Center clinical research unit.Twenty older adults with normal cognition (mean [SD] age, 69 [7] years) and 27 with amnestic mild cognitive impairment (67 [6] years).Randomization to a diet high in saturated fat content and with a high glycemic index (High diet; 45% of energy from fat [>25% saturated fat], 35%-40% from carbohydrates with a mean glycemic index >70, and 15%-20% from protein) or a diet low in saturated fat content and with a low glycemic index (Low diet; 25% of energy from fat [<7% saturated fat], 55%-60% from carbohydrates with a mean glycemic index <55, and 15%-20% from protein).Lipid-depleted A?42 and A?40 and apolipoprotein E in cerebrospinal fluid.Baseline levels of LD A? were greater for adults with mild cognitive impairment compared with adults with normal cognition (LD A?42, P = .05; LD A?40, P = .01). These findings were magnified in adults with mild cognitive impairment and the ?4 allele, who had higher LD apolipoprotein E levels irrespective of cognitive diagnosis (P < .001). The Low diet tended to decrease LD A? levels, whereas the High diet increased these fractions (LD A?42, P = .01; LD A?40, P = .15). Changes in LD A? levels with the Low diet negatively correlated with changes in cerebrospinal fluid levels of insulin (LD A?42 and insulin, r = -0.68 [P = .01]; LD A?40 and insulin, r = -0.78 [P = .002]).The lipidation states of apolipoproteins and A? peptides in the brain differ depending on APOE genotype and cognitive diagnosis. Concentrations can be modulated by diet. These findings may provide insight into the mechanisms through which apolipoprotein E4 and unhealthy diets impart risk for developing AD.

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

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