Amyloid-β protein modulates the perivascular clearance of neuronal apolipoprotein E in mouse models of Alzheimer's disease
| Autor: | Gerd Birkenmeier, Ajeet Rijal Upadhaya, Harshvardhan Rolyan, Dietmar Rudolf Thal, Ann Caroline Feike, Tom Van Dooren, Andreas Waha, Christian Haass, Claus U. Pietrzik, Fred Van Leuven |
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| Jazyk: | angličtina |
| Rok vydání: | 2011 |
| Předmět: |
Apolipoprotein E
metabolism [Tumor Suppressor Proteins] genetics [Gene Expression Regulation] Cerebral Ventricles metabolism [Apolipoproteins E] Neuroblastoma pathology [Alzheimer Disease] Mice Amyloid beta-Protein Precursor pathology [Brain] pathology [Neuroblastoma] Amyloid precursor protein metabolism [LDL-Receptor Related Protein-Associated Protein] LDL-Receptor Related Protein-Associated Protein Perivascular space Receptor physiopathology [Cerebral Ventricles] Neurons biology Brain genetics [Presenilin-1] Transfection Cell biology Psychiatry and Mental health medicine.anatomical_structure metabolism [Receptors LDL] Neurology Transcytosis genetics [Amyloid beta-Protein Precursor] metabolism [Neurons] Female lipids (amino acids peptides and proteins) Low Density Lipoprotein Receptor-Related Protein-1 physiopathology [Neuroblastoma] Genetically modified mouse metabolism [Amyloid beta-Peptides] Mice Transgenic Blood–brain barrier PSEN1 protein human Apolipoproteins E Alzheimer Disease Cell Line Tumor Glial Fibrillary Acidic Protein mental disorders Presenilin-1 medicine Animals Humans ddc:610 Biological Psychiatry Amyloid beta-Peptides Tumor Suppressor Proteins metabolism [Glial Fibrillary Acidic Protein] Disease Models Animal Lrp1 protein mouse Gene Expression Regulation Receptors LDL Immunology biology.protein genetics [Apolipoproteins E] Neurology (clinical) |
| Zdroj: | Journal of neural transmission 118(5), 699-712 (2011). doi:10.1007/s00702-010-0572-7 |
| DOI: | 10.1007/s00702-010-0572-7 |
| Popis: | 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. ispartof: Journal of Neural Transmission vol:118 issue:5 pages:699-712 ispartof: location:Austria status: published |
| Databáze: | OpenAIRE |
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