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In vivo human apolipoprotein E isoform fractional turnover rates in the CNS.

Wildsmith KR, Basak JM, Patterson BW, Pyatkivskyy Y, Kim J, Yarasheski KE, Wang JX, Mawuenyega KG, Jiang H, Parsadanian M, Yoon H, Kasten T, Sigurdson WC, Xiong C, Goate A, Holtzman DM, Bateman RJ - PLoS ONE (2012)

Bottom Line: No isoform-specific differences in CNS ApoE3 and ApoE4 turnover rates were observed when measured in human CSF or mouse brain.However, CNS and peripheral ApoE isoform turnover rates differed substantially, which is consistent with previous reports and suggests that the pathways responsible for ApoE metabolism are different in the CNS and the periphery.We also demonstrate a slower turnover rate for CSF ApoE than that for amyloid beta, another molecule critically important in AD pathogenesis.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology, Washington University School of Medicine, Saint Louis, Missouri, United States of America.

ABSTRACT
Apolipoprotein E (ApoE) is the strongest genetic risk factor for Alzheimer's disease and has been implicated in the risk for other neurological disorders. The three common ApoE isoforms (ApoE2, E3, and E4) each differ by a single amino acid, with ApoE4 increasing and ApoE2 decreasing the risk of Alzheimer's disease (AD). Both the isoform and amount of ApoE in the brain modulate AD pathology by altering the extent of amyloid beta (Aβ) peptide deposition. Therefore, quantifying ApoE isoform production and clearance rates may advance our understanding of the role of ApoE in health and disease. To measure the kinetics of ApoE in the central nervous system (CNS), we applied in vivo stable isotope labeling to quantify the fractional turnover rates of ApoE isoforms in 18 cognitively-normal adults and in ApoE3 and ApoE4 targeted-replacement mice. No isoform-specific differences in CNS ApoE3 and ApoE4 turnover rates were observed when measured in human CSF or mouse brain. However, CNS and peripheral ApoE isoform turnover rates differed substantially, which is consistent with previous reports and suggests that the pathways responsible for ApoE metabolism are different in the CNS and the periphery. We also demonstrate a slower turnover rate for CSF ApoE than that for amyloid beta, another molecule critically important in AD pathogenesis.

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CNS kinetic modeling curves.A, CNS-ApoE compartmental model was used to describe whole-system CNS-ApoE turnover kinetics. The model is based on data from plasma leucine and CSF-ApoE TTRs (solid triangles). The plasma leucine TTR time course for a given subject is used as a “forcing function” to define the tracer availability for ApoE synthesis. The CNS-ApoE system comprises a delay element and a compartment that turns over, and accounts for isotopic dilution of the plasma leucine. The model has 3 adjustable parameters: the shape of the ApoE TTR time course is modified by adjusting the delay time and the rate constant for ApoE turnover, and the magnitude of the ApoE TTR is scaled by varying the degree of isotopic dilution. B–D, A typical compartmental model analysis from a single, representative, ApoE3/3 subject. B, Plasma leucine TTR remains elevated and does not return to baseline enrichment immediately after the tracer infusion is halted. C–D, The ApoE TTR time course exhibits a long time delay and sigmoid rise to a peak enrichment which is well described by the model. C, ApoE3 peptide LAVYQAGAR; D, ApoE3 peptide LGADMEDVcGR. Solid line represents model fit to the data.
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pone-0038013-g004: CNS kinetic modeling curves.A, CNS-ApoE compartmental model was used to describe whole-system CNS-ApoE turnover kinetics. The model is based on data from plasma leucine and CSF-ApoE TTRs (solid triangles). The plasma leucine TTR time course for a given subject is used as a “forcing function” to define the tracer availability for ApoE synthesis. The CNS-ApoE system comprises a delay element and a compartment that turns over, and accounts for isotopic dilution of the plasma leucine. The model has 3 adjustable parameters: the shape of the ApoE TTR time course is modified by adjusting the delay time and the rate constant for ApoE turnover, and the magnitude of the ApoE TTR is scaled by varying the degree of isotopic dilution. B–D, A typical compartmental model analysis from a single, representative, ApoE3/3 subject. B, Plasma leucine TTR remains elevated and does not return to baseline enrichment immediately after the tracer infusion is halted. C–D, The ApoE TTR time course exhibits a long time delay and sigmoid rise to a peak enrichment which is well described by the model. C, ApoE3 peptide LAVYQAGAR; D, ApoE3 peptide LGADMEDVcGR. Solid line represents model fit to the data.

Mentions: The whole-system CNS-ApoE FTR was determined by fitting the full ApoE TTR time course to a compartmental model (Fig. 4A). Representative modeling curves are depicted in Fig. 4B–D and average kinetic rates for each genotype, grouped by peptide, are described in Table 2. The model provided a solid fit to the full ApoE TTR time course for all data sets (Fig. 4). No significant differences in kinetic parameters were observed between genotypes. In particular, there was no significant difference between ApoE isoform kinetics within either ApoE3/4 or ApoE2/4 heterozygotes. The whole-system FTR was 2.5±0.4%/h (n = 18, LAVYQAGAR). The monoexponential slope FCR was highly correlated (R2 = 0.71), and the FSR was less well correlated (R2 = 0.31), with the whole-system FTR.


In vivo human apolipoprotein E isoform fractional turnover rates in the CNS.

Wildsmith KR, Basak JM, Patterson BW, Pyatkivskyy Y, Kim J, Yarasheski KE, Wang JX, Mawuenyega KG, Jiang H, Parsadanian M, Yoon H, Kasten T, Sigurdson WC, Xiong C, Goate A, Holtzman DM, Bateman RJ - PLoS ONE (2012)

CNS kinetic modeling curves.A, CNS-ApoE compartmental model was used to describe whole-system CNS-ApoE turnover kinetics. The model is based on data from plasma leucine and CSF-ApoE TTRs (solid triangles). The plasma leucine TTR time course for a given subject is used as a “forcing function” to define the tracer availability for ApoE synthesis. The CNS-ApoE system comprises a delay element and a compartment that turns over, and accounts for isotopic dilution of the plasma leucine. The model has 3 adjustable parameters: the shape of the ApoE TTR time course is modified by adjusting the delay time and the rate constant for ApoE turnover, and the magnitude of the ApoE TTR is scaled by varying the degree of isotopic dilution. B–D, A typical compartmental model analysis from a single, representative, ApoE3/3 subject. B, Plasma leucine TTR remains elevated and does not return to baseline enrichment immediately after the tracer infusion is halted. C–D, The ApoE TTR time course exhibits a long time delay and sigmoid rise to a peak enrichment which is well described by the model. C, ApoE3 peptide LAVYQAGAR; D, ApoE3 peptide LGADMEDVcGR. Solid line represents model fit to the data.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3366983&req=5

pone-0038013-g004: CNS kinetic modeling curves.A, CNS-ApoE compartmental model was used to describe whole-system CNS-ApoE turnover kinetics. The model is based on data from plasma leucine and CSF-ApoE TTRs (solid triangles). The plasma leucine TTR time course for a given subject is used as a “forcing function” to define the tracer availability for ApoE synthesis. The CNS-ApoE system comprises a delay element and a compartment that turns over, and accounts for isotopic dilution of the plasma leucine. The model has 3 adjustable parameters: the shape of the ApoE TTR time course is modified by adjusting the delay time and the rate constant for ApoE turnover, and the magnitude of the ApoE TTR is scaled by varying the degree of isotopic dilution. B–D, A typical compartmental model analysis from a single, representative, ApoE3/3 subject. B, Plasma leucine TTR remains elevated and does not return to baseline enrichment immediately after the tracer infusion is halted. C–D, The ApoE TTR time course exhibits a long time delay and sigmoid rise to a peak enrichment which is well described by the model. C, ApoE3 peptide LAVYQAGAR; D, ApoE3 peptide LGADMEDVcGR. Solid line represents model fit to the data.
Mentions: The whole-system CNS-ApoE FTR was determined by fitting the full ApoE TTR time course to a compartmental model (Fig. 4A). Representative modeling curves are depicted in Fig. 4B–D and average kinetic rates for each genotype, grouped by peptide, are described in Table 2. The model provided a solid fit to the full ApoE TTR time course for all data sets (Fig. 4). No significant differences in kinetic parameters were observed between genotypes. In particular, there was no significant difference between ApoE isoform kinetics within either ApoE3/4 or ApoE2/4 heterozygotes. The whole-system FTR was 2.5±0.4%/h (n = 18, LAVYQAGAR). The monoexponential slope FCR was highly correlated (R2 = 0.71), and the FSR was less well correlated (R2 = 0.31), with the whole-system FTR.

Bottom Line: No isoform-specific differences in CNS ApoE3 and ApoE4 turnover rates were observed when measured in human CSF or mouse brain.However, CNS and peripheral ApoE isoform turnover rates differed substantially, which is consistent with previous reports and suggests that the pathways responsible for ApoE metabolism are different in the CNS and the periphery.We also demonstrate a slower turnover rate for CSF ApoE than that for amyloid beta, another molecule critically important in AD pathogenesis.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology, Washington University School of Medicine, Saint Louis, Missouri, United States of America.

ABSTRACT
Apolipoprotein E (ApoE) is the strongest genetic risk factor for Alzheimer's disease and has been implicated in the risk for other neurological disorders. The three common ApoE isoforms (ApoE2, E3, and E4) each differ by a single amino acid, with ApoE4 increasing and ApoE2 decreasing the risk of Alzheimer's disease (AD). Both the isoform and amount of ApoE in the brain modulate AD pathology by altering the extent of amyloid beta (Aβ) peptide deposition. Therefore, quantifying ApoE isoform production and clearance rates may advance our understanding of the role of ApoE in health and disease. To measure the kinetics of ApoE in the central nervous system (CNS), we applied in vivo stable isotope labeling to quantify the fractional turnover rates of ApoE isoforms in 18 cognitively-normal adults and in ApoE3 and ApoE4 targeted-replacement mice. No isoform-specific differences in CNS ApoE3 and ApoE4 turnover rates were observed when measured in human CSF or mouse brain. However, CNS and peripheral ApoE isoform turnover rates differed substantially, which is consistent with previous reports and suggests that the pathways responsible for ApoE metabolism are different in the CNS and the periphery. We also demonstrate a slower turnover rate for CSF ApoE than that for amyloid beta, another molecule critically important in AD pathogenesis.

Show MeSH
Related in: MedlinePlus