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Endogenous Apolipoprotein E (ApoE) Fragmentation Is Linked to Amyloid Pathology in Transgenic Mouse Models of Alzheimer’s Disease

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Abstract

The epsilon 4 allele of the apolipoprotein E (ApoE4) gene is the most important risk factor implicated in Alzheimer’s disease (AD) etiology. ApoE4 is more susceptible to proteolysis, and ApoE fragments have been shown to promote tau hyperphosphorylation and exert neurotoxic properties. While a plethora of studies deals with the effect of ApoE and its fragments on amyloid-β peptide (Aβ) deposition and clearance, it is largely unknown whether Aβ in turn influences human or murine ApoE expression and its proteolysis. The present study is the first to show that endogenous murine ApoE becomes proteolytically processed in a way reminiscent of human ApoE fragmentation in different AD mouse models, including APP/PS1KI or 5XFAD. Murine ApoE fragments were demonstrated to accumulate mainly in synaptic fractions in AD mouse models. In vitro experiments, as well as analysis of mouse models at different time points, suggest that the amount of total ApoE is associated with extracellular Aβ while the amount of its fragments is linked to intracellular Aβ levels. Murine ApoE fragmentation is a common feature in different AD transgenic mouse models and could be directly associated with intraneuronal Aβ accumulation. Extracellular amyloid induces an elevation in full-length ApoE expression, which might present a protective mechanism toward Aβ clearance. The demonstrated fragments of murine ApoE in vitro and in vivo might therefore play a crucial role in the progression of AD pathology in murine AD models.

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Acknowledgments

This work was supported by the Alzheimer Forschung Initiative e.V. (to O.W., grant #12802).

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  1. Division of Molecular Psychiatry, Department of Psychiatry and Psychotherapy, University Medical Center (UMG), Georg-August-University, von-Siebold-Str. 5, Goettingen, 37075, Germany

    Anika Saul & Oliver Wirths

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Correspondence to Oliver Wirths.

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All procedures were performed according to German guidelines for animal care and approved by the University of Goettingen Medical Center Institutional Animal Care and Use Committee.

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Supplemental Fig. 1. ApoE fragmentation in APPPS1-21 mice. Supplemental Fig. 2. ApoE fragments accumulate in synaptosomes of APP/PS1KI mice. (PDF 306 kb)

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Saul, A., Wirths, O. Endogenous Apolipoprotein E (ApoE) Fragmentation Is Linked to Amyloid Pathology in Transgenic Mouse Models of Alzheimer’s Disease. Mol Neurobiol 54, 319–327 (2017). https://doi.org/10.1007/s12035-015-9674-4

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