ApoE facilitates the microglial response to amyloid plaque pathology

Jason D. Ulrich, Tyler K. Ulland, Thomas E. Mahan, Sofie Nyström, K. Peter Nilsson, Wilbur M. Song, Yingyue Zhou, Mariska Reinartz, Seulah Choi, Hong Jiang, Floy R. Stewart, Elise Anderson, Yaming Wang, Marco Colonna, David M. Holtzman

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53 Scopus citations

Abstract

One of the hallmarks of Alzheimer's disease is the presence of extracellular diffuse and fibrillar plaques predominantly consisting of the amyloid-β (Aβ) peptide. Apolipoprotein E (ApoE) influences the deposition of amyloid pathology through affecting the clearance and aggregation of monomeric Aβ in the brain. In addition to influencing Aβ metabolism, increasing evidence suggests that apoE influences microglial function in neurodegenerative diseases. Here, we characterize the impact that apoE has on amyloid pathology and the innate immune response in APP PS1ΔE9 and APP PS1-21 transgenic mice. We report that Apoe deficiency reduced fibrillar plaque deposition, consistent with previous studies. However, fibrillar plaques in Apoe-deficient mice exhibited a striking reduction in plaque compaction. Hyperspectral fluorescent imaging using luminescent conjugated oligothiophenes identified distinct Aβ morphotypes in Apoe-deficient mice. We also observed a significant reduction in fibrillar plaque-associated microgliosis and activated microglial gene expression in Apoe-deficient mice, along with significant increases in dystrophic neurites around fibrillar plaques. Our results suggest that apoE is critical in stimulating the innate immune response to amyloid pathology.

Original languageEnglish
Pages (from-to)1047-1058
Number of pages12
JournalJournal of Experimental Medicine
Volume215
Issue number4
DOIs
StatePublished - Apr 1 2018

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    Ulrich, J. D., Ulland, T. K., Mahan, T. E., Nyström, S., Peter Nilsson, K., Song, W. M., Zhou, Y., Reinartz, M., Choi, S., Jiang, H., Stewart, F. R., Anderson, E., Wang, Y., Colonna, M., & Holtzman, D. M. (2018). ApoE facilitates the microglial response to amyloid plaque pathology. Journal of Experimental Medicine, 215(4), 1047-1058. https://doi.org/10.1084/jem.20171265