ApoE Promotes the Proteolytic Degradation of Aβ

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

Research output: Contribution to journalArticle

568 Citations (Scopus)

Abstract

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

Original languageEnglish (US)
Pages (from-to)681-693
Number of pages13
JournalNeuron
Volume58
Issue number5
DOIs
StatePublished - Jun 12 2008
Externally publishedYes

Fingerprint

Apolipoproteins E
Brain
Insulysin
Neprilysin
Memory Disorders
Microglia
Alzheimer Disease
Protein Isoforms
Homeostasis
Peptides
Enzymes

Keywords

  • CELLBIO
  • HUMDISEASE
  • MOLNEURO

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Jiang, Q., Lee, C. Y. D., Mandrekar, S., Wilkinson, B., Cramer, P., Zelcer, N., ... Landreth, G. E. (2008). ApoE Promotes the Proteolytic Degradation of Aβ. Neuron, 58(5), 681-693. https://doi.org/10.1016/j.neuron.2008.04.010

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

In: Neuron, Vol. 58, No. 5, 12.06.2008, p. 681-693.

Research output: Contribution to journalArticle

Jiang, Q, Lee, CYD, Mandrekar, S, Wilkinson, B, Cramer, P, Zelcer, N, Mann, K, Lamb, B, Willson, TM, Collins, JL, Richardson, JC, Smith, JD, Comery, TA, Riddell, D, Holtzman, DM, Tontonoz, P & Landreth, GE 2008, 'ApoE Promotes the Proteolytic Degradation of Aβ', Neuron, vol. 58, no. 5, pp. 681-693. https://doi.org/10.1016/j.neuron.2008.04.010
Jiang Q, Lee CYD, Mandrekar S, Wilkinson B, Cramer P, Zelcer N et al. ApoE Promotes the Proteolytic Degradation of Aβ. Neuron. 2008 Jun 12;58(5):681-693. https://doi.org/10.1016/j.neuron.2008.04.010
Jiang, Qingguang ; Lee, C. Y Daniel ; Mandrekar, Shweta ; Wilkinson, Brandy ; Cramer, Paige ; Zelcer, Noam ; Mann, Karen ; Lamb, Bruce ; Willson, Timothy M. ; Collins, Jon L. ; Richardson, Jill C. ; Smith, Jonathan D. ; Comery, Thomas A. ; Riddell, David ; Holtzman, David M. ; Tontonoz, Peter ; Landreth, Gary E. / ApoE Promotes the Proteolytic Degradation of Aβ. In: Neuron. 2008 ; Vol. 58, No. 5. pp. 681-693.
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