Overexpression of Low-Density Lipoprotein Receptor in the Brain Markedly Inhibits Amyloid Deposition and Increases Extracellular Aβ Clearance

Jungsu Kim, Joseph M. Castellano, Hong Jiang, Jacob M. Basak, Maia Parsadanian, Vi Pham, Stephanie M. Mason, Steven M. Paul, David M. Holtzman

Research output: Contribution to journalArticle

141 Scopus citations

Abstract

Apolipoprotein E (APOE) is the strongest genetic risk factor for Alzheimer's disease (AD). Previous studies suggest that the effect of apoE on amyloid-β (Aβ) accumulation plays a major role in AD pathogenesis. Therefore, understanding proteins that control apoE metabolism may provide new targets for regulating Aβ levels. LDLR, a member of the LDL receptor family, binds to apoE, yet its potential role in AD pathogenesis remains unclear. We hypothesized that LDLR overexpression in the brain would decrease apoE levels, enhance Aβ clearance, and decrease Aβ deposition. To test our hypothesis, we created several transgenic mice that overexpress LDLR in the brain and found that apoE levels in these mice decreased by 50%-90%. Furthermore, LDLR overexpression dramatically reduced Aβ aggregation and enhanced Aβ clearance from the brain extracellular space. Plaque-associated neuroinflammatory responses were attenuated in LDLR transgenic mice. These findings suggest that increasing LDLR levels may represent a novel AD treatment strategy.

Original languageEnglish (US)
Pages (from-to)632-644
Number of pages13
JournalNeuron
Volume64
Issue number5
DOIs
StatePublished - Dec 10 2009

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Keywords

  • humdisease
  • molneuro

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Kim, J., Castellano, J. M., Jiang, H., Basak, J. M., Parsadanian, M., Pham, V., Mason, S. M., Paul, S. M., & Holtzman, D. M. (2009). Overexpression of Low-Density Lipoprotein Receptor in the Brain Markedly Inhibits Amyloid Deposition and Increases Extracellular Aβ Clearance. Neuron, 64(5), 632-644. https://doi.org/10.1016/j.neuron.2009.11.013