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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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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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 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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DOI: https://doi.org/10.1038/nm1058
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