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The Journal of Neuroscience, March 18, 2009, 29(11):3603-3612; doi:10.1523/JNEUROSCI.5302-08.2009

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Neurobiology of Disease
Macrophage-Mediated Degradation of β-Amyloid via an Apolipoprotein E Isoform-Dependent Mechanism

Lingzhi Zhao,^1 * Suizhen Lin,^1 * Kelly R. Bales,¹ Valentina Gelfanova,² Deanna Koger,¹ Cynthia DeLong,¹ John Hale,² Feng Liu,¹ Jesse M. Hunter,¹ and Steven M. Paul¹

¹Neuroscience Discovery Research and ²Integrative Biology, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285

Correspondence should be addressed to Dr. Steven M. Paul, Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285. Email: Paul_Steven_M{at}Lilly.com

Recent studies suggest that bone marrow-derived macrophages can effectively reduce β-amyloid (Aβ) deposition in brain. To further elucidate the mechanisms by which macrophages degrade Aβ, we cultured murine macrophages on top of Aβ plaque-bearing brain sections from transgenic mice expressing PDAPP [human amyloid precursor protein (APP) with the APP_717V>F mutation driven by the platelet-derived growth factor promoter]. Using this ex vivo assay, we found that macrophages from wild-type mice very efficiently degrade both soluble and insoluble Aβ in a time-dependent manner and markedly eliminate thioflavine-S positive amyloid deposits. Because macrophages express and secrete apolipoprotein E (apoE), we compared the efficiency of Aβ degradation by macrophages prepared from apoE-deficient mice or mice expressing human apoE2, apoE3, or apoE4. Macrophages expressing apoE2 were more efficient at degrading Aβ than apoE3-expressing, apoE4-expressing, or apoE-deficient macrophages. Moreover, macrophage-induced degradation of Aβ was effectively blocked by an anti-apoE antibody and receptor-associated protein, an antagonist of the low-density lipoprotein (LDL) receptor family, suggesting involvement of LDL receptors. Measurement of matrix metalloproteinase-9 (MMP-9) activity in the media from human apoE-expressing macrophages cocultured with Aβ-containing brain sections revealed greater levels of MMP-9 activity in apoE2-expressing than in either apoE3- or apoE4-expressing macrophages. Differences in MMP-9 activity appear to contribute to the isoform-specific differences in Aβ degradation by macrophages. These apoE isoform-dependent effects of macrophages on Aβ degradation suggest a novel "peripheral" mechanism for Aβ clearance from brain that may also, in part, explain the isoform-dependent effects of apoE in determining the genetic risk for Alzheimer's disease.

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Received Nov. 4, 2008; revised Jan. 25, 2009; accepted Feb. 9, 2009.

Correspondence should be addressed to Dr. Steven M. Paul, Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285. Email: Paul_Steven_M{at}Lilly.com

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