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Microglial activation by Alzheimer amyloid precursor protein and modulation by apolipoprotein E

Nature volume 388, pages 878–881 (1997)Cite this article

Abstract

A role for β-amyloid precursor protein (β-APP) in the development of Alzheimer's disease has been indicated by genetics1, and many conditions in which β-APP is raised have been associated with an increased risk of Alzheimer's disease or an Alzheimer's-like pathology2,3,4. Inflammatory events may also contribute to Alzheimer's disease5. Here we investigate whether a secreted derivative of β-APP (sAPP-α) can induce inflammatory reactions in microglia, which are brain cells of monocytic lineage. We found that treatment with sAPP-α increased markers of activation in microglia and enhanced their production of neurotoxins. The ability of sAPP-α to activate microglia was blocked by prior incubation of the protein with apolipoprotein E3 but not apolipoprotein E4, a variant associated with an increased risk for Alzheimer's6. A product of amyloidogenic β-APP processing (sAPP-β) also activated microglia. Because sAPP-β is deficient in the neuroprotective activity shown by sAPP-α, our results indicate that increased amyloidogenic processing could adversely affect the balance of sAPP activities that determine neuronal viability.

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Figure 1: Activation of NF-κB in N9 microglial cells by sAPPN9 cultures were treated for 90 min with control buffer or 5 nM sAPP (sAPP), and nuclear extracts were assayed by EMSA with a κB DNA probe.
Figure 2: Increase in IL-1β and iNOS in microglial cells by sAPP.
Figure 3: Structural requirements for sAPP stimulation of microglia.
Figure 4: Interaction between ApoE and sAPP.

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Acknowledgements

We are indebted to Paola Ricciardi-Castagnoli for the N9 cell line, to D. Davies for advice on microglial culture techniques, to M. Lucas for technical assistance, and to S. Griffin and M. J. LaDu for helpful comments. This work was supported by funds granted to S.W.B. by the Inglewood Foundation, NIH (NINDS), Alzheimer's Association, and a UAMS pilot project award.

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  1. Department of Geriatrics, and Department of Anatomy, Cell Biology, and Neurobiology, University of Arkansas for Medical Sciences, Little Rock, 72205, Arkansas, USA

    Steven W. Barger

  2. Geriatric Research Education and Clinical Center, John L. McClellan Memorial Veterans Affairs Medical Center, Little Rock, 72205, Arkansas, USA

    Steven W. Barger & Ashley D. Harmon

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Correspondence to Steven W. Barger.

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Barger, S., Harmon, A. Microglial activation by Alzheimer amyloid precursor protein and modulation by apolipoprotein E. Nature 388, 878–881 (1997). https://doi.org/10.1038/42257

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