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Apolipoprotein E promotes astrocyte colocalization and degradation of deposited amyloid-β peptides

Nature Medicine volume 10, pages 719–726 (2004)Cite this article

Abstract

We 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-β peptides (Aβ) in a mouse model of Alzheimer disease. Given the capacity of astrocytes to degrade Aβ, 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 Aβ present in Aβ plaque–bearing brain sections in vitro. Coincubation with antibodies to either Apoe or Aβ, or with RAP, an antagonist of the low-density lipoprotein receptor family, effectively blocks Aβ degradation by astrocytes. Phase-contrast and confocal microscopy show that Apoe−/− astrocytes do not respond to or internalize Aβ deposits to the same extent as do wild-type astrocytes. Thus, Apoe seems to be important in the degradation and clearance of deposited Aβ species by astrocytes, a process that may be impaired in Alzheimer disease.

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Figure 1: Apoe is essential for the degradation of Aβ by adult astrocytes.
Figure 2: Antibodies to Apoe and Aβ block degradation of Aβ.
Figure 3: Adult wild-type astrocytes aggregate and form extended processes.
Figure 4: Apoe is important for astrocytes to associate with Aβ.
Figure 5: Multicellular aggregates of astrocytes are associated with loss of Aβ.
Figure 6: Adult wild-type astrocytes associate with and internalize human Aβ.

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Acknowledgements

We thank R. DeMattos for comments. M.K. was supported, in part, by the Saastamoinen Foundation and the Finnish Cultural Foundation of Northern Savo, Kuopio, Finland.

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Author notes

  1. Milla Koistinaho and Suizhen Lin: These authors contributed equally to this work.

Authors and Affiliations

  1. Neuroscience Discovery Research, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, 46285, Indiana, USA

    Milla Koistinaho, Suizhen Lin, Xin Wu, Deanna Koger, Feng Liu, Seema Malkani, Kelly R Bales & Steven M Paul

  2. Discovery Information Technology, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, 46285, Indiana, USA

    Michail Esterman & Jeffrey Hanson

  3. Genomics Informatics-Statistics, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, 46285, Indiana, USA

    Richard Higgs

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Correspondence to Steven M Paul.

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Competing interests

S.L., X.W., M.E., D.K., J.H., R.H., F.L., S.M., K.R.B. and S.M.P. are employees of Eli Lilly and Company, and several of them own stock in the company.

Supplementary information

Supplementary Figure 1 (PDF 179 kb)

Supplementary Figure 2

Preincubation of tissue sections or astrocytes with anti-Apoe antibosy fails to block astrocyte-mediated Aβ degradation. (PDF 158 kb)

Supplementary Figure 3

Adult WT astrocytes aggregate and form extended processes when exposed to PDAPP mouse brain sections. (PDF 450 kb)

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Koistinaho, M., Lin, S., Wu, X. et al. Apolipoprotein E promotes astrocyte colocalization and degradation of deposited amyloid-β peptides. Nat Med 10, 719–726 (2004). https://doi.org/10.1038/nm1058

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