Nature Medicine
10, 719 - 726 (2004)
Published online: 13 June 2004; | doi:10.1038/nm1058
Apolipoprotein E promotes astrocyte colocalization and degradation of deposited amyloid- peptidesMilla Koistinaho1, 4, Suizhen Lin1, 4, Xin Wu1, Michail Esterman2, Deanna Koger1, Jeffrey Hanson2, Richard Higgs3, Feng Liu1, Seema Malkani1, Kelly R Bales1
& Steven M Paul11
Neuroscience Discovery Research, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285, USA. 2
Discovery Information Technology, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285, USA. 3
Genomics Informatics-Statistics, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285, USA. 4
These authors contributed equally to this work.
Correspondence should be addressed to Steven M Paul Paul_Steven_M@Lilly.comWe have previously shown that apolipoprotein E (Apoe) promotes the formation of amyloid in brain and that astrocyte-specific expression of APOE markedly affects the deposition of amyloid- peptides (A) in a mouse model of Alzheimer disease. Given the capacity of astrocytes to degrade A, we investigated the potential role of Apoe in this astrocyte-mediated degradation. In contrast to cultured adult wild-type mouse astrocytes, adult Apoe-/- astrocytes do not degrade A present in A plaque−bearing brain sections in vitro. Coincubation with antibodies to either Apoe or A, or with RAP, an antagonist of the low-density lipoprotein receptor family, effectively blocks A degradation by astrocytes. Phase-contrast and confocal microscopy show that Apoe-/- astrocytes do not respond to or internalize A deposits to the same extent as do wild-type astrocytes. Thus, Apoe seems to be important in the degradation and clearance of deposited A species by astrocytes, a process that may be impaired in Alzheimer disease.
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