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Amyloid-β protein modulates the perivascular clearance of neuronal apolipoprotein E in mouse models of Alzheimer's disease.
J Neural Transm (Vienna). 2011 May; 118(5):699-712.JN

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 α(2)macroglobulin 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.

Authors+Show Affiliations

Laboratory of Neuropathology, Institute of Pathology, University of Ulm, Ulm, Germany.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

21210284

Citation

Rolyan, Harshvardhan, et al. "Amyloid-β Protein Modulates the Perivascular Clearance of Neuronal Apolipoprotein E in Mouse Models of Alzheimer's Disease." Journal of Neural Transmission (Vienna, Austria : 1996), vol. 118, no. 5, 2011, pp. 699-712.
Rolyan H, Feike AC, Upadhaya AR, et al. Amyloid-β protein modulates the perivascular clearance of neuronal apolipoprotein E in mouse models of Alzheimer's disease. J Neural Transm (Vienna). 2011;118(5):699-712.
Rolyan, H., Feike, A. C., Upadhaya, A. R., Waha, A., Van Dooren, T., Haass, C., Birkenmeier, G., Pietrzik, C. U., Van Leuven, F., & Thal, D. R. (2011). Amyloid-β protein modulates the perivascular clearance of neuronal apolipoprotein E in mouse models of Alzheimer's disease. Journal of Neural Transmission (Vienna, Austria : 1996), 118(5), 699-712. https://doi.org/10.1007/s00702-010-0572-7
Rolyan H, et al. Amyloid-β Protein Modulates the Perivascular Clearance of Neuronal Apolipoprotein E in Mouse Models of Alzheimer's Disease. J Neural Transm (Vienna). 2011;118(5):699-712. PubMed PMID: 21210284.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Amyloid-β protein modulates the perivascular clearance of neuronal apolipoprotein E in mouse models of Alzheimer's disease. AU - Rolyan,Harshvardhan, AU - Feike,Ann Caroline, AU - Upadhaya,Ajeet Rijal, AU - Waha,Andreas, AU - Van Dooren,Tom, AU - Haass,Christian, AU - Birkenmeier,Gerd, AU - Pietrzik,Claus U, AU - Van Leuven,Fred, AU - Thal,Dietmar Rudolf, Y1 - 2011/01/06/ PY - 2010/08/30/received PY - 2010/12/17/accepted PY - 2011/1/7/entrez PY - 2011/1/7/pubmed PY - 2011/9/9/medline SP - 699 EP - 712 JF - Journal of neural transmission (Vienna, Austria : 1996) JO - J Neural Transm (Vienna) VL - 118 IS - 5 N2 - 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 α(2)macroglobulin 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. SN - 1435-1463 UR - https://www.unboundmedicine.com/medline/citation/21210284/Amyloid_β_protein_modulates_the_perivascular_clearance_of_neuronal_apolipoprotein_E_in_mouse_models_of_Alzheimer's_disease_ L2 - https://doi.org/10.1007/s00702-010-0572-7 DB - PRIME DP - Unbound Medicine ER -