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Amyloid-β protein modulates the perivascular clearance of neuronal apolipoprotein E in mouse models of Alzheimer’s disease

  • Dementias - Original Article
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Abstract

The deposition of amyloid-β protein (Aβ) in the brain is a hallmark of Alzheimer’s disease (AD). Apolipoprotein E (apoE) is involved in the clearance of Aβ from brain and the APOE ε4 allele is a major risk factor for sporadic AD. We have recently shown that apoE is drained into the perivascular space (PVS), where it co-localizes with Aβ. To further clarify the role of apoE in perivascular clearance of Aβ, we studied apoE-transgenic mice over-expressing human apoE4 either in astrocytes (GE4) or in neurons (TE4). These animals were crossbred with amyloid precursor protein (APP)-transgenic mice and with APP-presenilin-1 (APP-PS1) double transgenic mice. Using an antibody that specifically detects human apoE (h-apoE), we observed that astroglial expression of h-apoE in GE4 mice leads to its perivascular drainage, whereas neuronal expression in TE4 mice does not, indicating that neuron-derived apoE is usually not the subject of perivascular drainage. However, h-apoE was observed not only in the PVS of APP-GE4 and APP-PS1-GE4 mice, but also in that of APP-TE4 and APP-PS1-TE4 mice. In all these mouse lines, we found co-localization of neuron-derived h-apoE and Aβ in the PVS. Aβ and h-apoE were also found in the cytoplasm of perivascular astrocytes indicating that astrocytes take up the neuron-derived apoE bound to Aβ, presumably prior to its clearance into the PVS. The uptake of apoE–Aβ complexes into glial cells was further investigated in glioblastoma cells. It was mediated by α2macroglobulin receptor/low density lipoprotein receptor-related protein (LRP-1) and inhibited by adding receptor-associated protein (RAP). It results in endosomal Aβ accumulation within these cells. These results suggest that neuronal apoE–Aβ complexes, but not neuronal apoE alone, are substrates for LRP-1-mediated astroglial uptake, transcytosis, and subsequent perivascular drainage. Thus, the production of Aβ and its interaction with apoE lead to the pathological perivascular drainage of neuronal apoE and provide insight into the pathological interactions of Aβ with neuronal apoE metabolism.

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Acknowledgments

This study was supported by the DFG (TH624/6-1) and BONFOR. The authors thank Mrs. Irina Lungrin for technical help.

Conflict of interest

Tom van Dooren is an employee of reMYND nv, Bioincubator, G. Geenslaan 1, B-3000 Leuven, Belgium.

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  1. Tom Van Dooren

    Present address: reMYND nv, Bioincubator, G. Geenslaan 1, 3000, Leuven, Belgium

Authors and Affiliations

  1. Laboratory of Neuropathology, Institute of Pathology, University of Ulm, Helmholtzstrasse 8/1, 89081, Ulm, Germany

    Harshvardhan Rolyan, Ajeet Rijal Upadhaya & Dietmar Rudolf Thal

  2. Department of Neuropathology, University of Bonn, Bonn, Germany

    Ann Caroline Feike, Andreas Waha & Dietmar Rudolf Thal

  3. Experimental Genetics Group- LEGTEGG, Department of Human Genetics, Catholic University Leuven, Leuven, Belgium

    Tom Van Dooren & Fred Van Leuven

  4. DZNE-German Center for Neurodegenerative Diseases, Munich and Adolf-Butenandt-Institute, Biochemistry, Ludwig-Maximilians-University, Munich, Germany

    Christian Haass

  5. Department of Biochemistry, University of Leipzig, Leipzig, Germany

    Gerd Birkenmeier

  6. Institute of Physiological Chemistry and Pathobiochemistry, Molecular Neurodegeneration, University of Mainz, Mainz, Germany

    Claus U. Pietrzik

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  1. Harshvardhan Rolyan
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Correspondence to Dietmar Rudolf Thal.

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Rolyan, H., Feike, A.C., Upadhaya, A.R. et al. Amyloid-β protein modulates the perivascular clearance of neuronal apolipoprotein E in mouse models of Alzheimer’s disease. J Neural Transm 118, 699–712 (2011). https://doi.org/10.1007/s00702-010-0572-7

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