ApoE promotes the proteolytic degradation of Abeta

Qingguang Jiang; C. Y. Daniel Lee; Shweta Mandrekar; Brandy Wilkinson; Paige Cramer; Noam Zelcer; Karen Mann; Bruce Lamb; Timothy M. Willson; Jon L. Collins; Jill C. Richardson; Jonathan D. Smith; Thomas A. Comery; David Riddell; David M. Holtzman; Peter Tontonoz; Gary E. Landreth

doi:https://doi.org/10.1016/j.neuron.2008.04.010

ApoE promotes the proteolytic degradation of Abeta

Qingguang Jiang, C. Y. Daniel Lee, Shweta Mandrekar, Brandy Wilkinson, Paige Cramer, Noam Zelcer, Karen Mann, Bruce Lamb, Timothy M. Willson, Jon L. Collins, Jill C. Richardson, Jonathan D. Smith, Thomas A. Comery, David Riddell, David M. Holtzman, Peter Tontonoz, Gary E. Landreth

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Research output: Contribution to journal › Article › Academic › peer-review

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Abstract

Apolipoprotein E is associated with age-related risk for Alzheimer's disease and plays critical roles in Abeta homeostasis. We report that ApoE plays a role in facilitating the proteolytic clearance of soluble Abeta from the brain. The endolytic degradation of Abeta peptides within microglia by neprilysin and related enzymes is dramatically enhanced by ApoE. Similarly, Abeta degradation extracellularly by insulin-degrading enzyme is facilitated by ApoE. The capacity of ApoE to promote Abeta degradation is dependent upon the ApoE isoform and its lipidation status. The enhanced expression of lipidated ApoE, through the activation of liver X receptors, stimulates Abeta degradation. Indeed, aged Tg2576 mice treated with the LXR agonist GW3965 exhibited a dramatic reduction in brain Abeta load. GW3965 treatment also reversed contextual memory deficits. These data demonstrate a mechanism through which ApoE facilitates the clearance of Abeta from the brain and suggest that LXR agonists may represent a novel therapy for AD

Original language	English
Pages (from-to)	681-693
Journal	Neuron
Volume	58
Issue number	5
DOIs	https://doi.org/10.1016/j.neuron.2008.04.010
Publication status	Published - 2008

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https://doi.org/10.1016/j.neuron.2008.04.010

Cite this

Jiang, Q., Lee, C. Y. D., Mandrekar, S., Wilkinson, B., Cramer, P., Zelcer, N., Mann, K., Lamb, B., Willson, T. M., Collins, J. L., Richardson, J. C., Smith, J. D., Comery, T. A., Riddell, D., Holtzman, D. M., Tontonoz, P., & Landreth, G. E. (2008). ApoE promotes the proteolytic degradation of Abeta. Neuron, 58(5), 681-693. https://doi.org/10.1016/j.neuron.2008.04.010

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title = "ApoE promotes the proteolytic degradation of Abeta",

abstract = "Apolipoprotein E is associated with age-related risk for Alzheimer's disease and plays critical roles in Abeta homeostasis. We report that ApoE plays a role in facilitating the proteolytic clearance of soluble Abeta from the brain. The endolytic degradation of Abeta peptides within microglia by neprilysin and related enzymes is dramatically enhanced by ApoE. Similarly, Abeta degradation extracellularly by insulin-degrading enzyme is facilitated by ApoE. The capacity of ApoE to promote Abeta degradation is dependent upon the ApoE isoform and its lipidation status. The enhanced expression of lipidated ApoE, through the activation of liver X receptors, stimulates Abeta degradation. Indeed, aged Tg2576 mice treated with the LXR agonist GW3965 exhibited a dramatic reduction in brain Abeta load. GW3965 treatment also reversed contextual memory deficits. These data demonstrate a mechanism through which ApoE facilitates the clearance of Abeta from the brain and suggest that LXR agonists may represent a novel therapy for AD",

author = "Qingguang Jiang and Lee, {C. Y. Daniel} and Shweta Mandrekar and Brandy Wilkinson and Paige Cramer and Noam Zelcer and Karen Mann and Bruce Lamb and Willson, {Timothy M.} and Collins, {Jon L.} and Richardson, {Jill C.} and Smith, {Jonathan D.} and Comery, {Thomas A.} and David Riddell and Holtzman, {David M.} and Peter Tontonoz and Landreth, {Gary E.}",

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T1 - ApoE promotes the proteolytic degradation of Abeta

AU - Jiang, Qingguang

AU - Lee, C. Y. Daniel

AU - Mandrekar, Shweta

AU - Wilkinson, Brandy

AU - Cramer, Paige

AU - Zelcer, Noam

AU - Mann, Karen

AU - Lamb, Bruce

AU - Willson, Timothy M.

AU - Collins, Jon L.

AU - Richardson, Jill C.

AU - Smith, Jonathan D.

AU - Comery, Thomas A.

AU - Riddell, David

AU - Holtzman, David M.

AU - Tontonoz, Peter

AU - Landreth, Gary E.

PY - 2008

Y1 - 2008

N2 - Apolipoprotein E is associated with age-related risk for Alzheimer's disease and plays critical roles in Abeta homeostasis. We report that ApoE plays a role in facilitating the proteolytic clearance of soluble Abeta from the brain. The endolytic degradation of Abeta peptides within microglia by neprilysin and related enzymes is dramatically enhanced by ApoE. Similarly, Abeta degradation extracellularly by insulin-degrading enzyme is facilitated by ApoE. The capacity of ApoE to promote Abeta degradation is dependent upon the ApoE isoform and its lipidation status. The enhanced expression of lipidated ApoE, through the activation of liver X receptors, stimulates Abeta degradation. Indeed, aged Tg2576 mice treated with the LXR agonist GW3965 exhibited a dramatic reduction in brain Abeta load. GW3965 treatment also reversed contextual memory deficits. These data demonstrate a mechanism through which ApoE facilitates the clearance of Abeta from the brain and suggest that LXR agonists may represent a novel therapy for AD

AB - Apolipoprotein E is associated with age-related risk for Alzheimer's disease and plays critical roles in Abeta homeostasis. We report that ApoE plays a role in facilitating the proteolytic clearance of soluble Abeta from the brain. The endolytic degradation of Abeta peptides within microglia by neprilysin and related enzymes is dramatically enhanced by ApoE. Similarly, Abeta degradation extracellularly by insulin-degrading enzyme is facilitated by ApoE. The capacity of ApoE to promote Abeta degradation is dependent upon the ApoE isoform and its lipidation status. The enhanced expression of lipidated ApoE, through the activation of liver X receptors, stimulates Abeta degradation. Indeed, aged Tg2576 mice treated with the LXR agonist GW3965 exhibited a dramatic reduction in brain Abeta load. GW3965 treatment also reversed contextual memory deficits. These data demonstrate a mechanism through which ApoE facilitates the clearance of Abeta from the brain and suggest that LXR agonists may represent a novel therapy for AD

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DO - https://doi.org/10.1016/j.neuron.2008.04.010

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SN - 0896-6273

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JO - Neuron

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