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

作者：Rolyan Harshvardhan; Feike Ann Caroline; Upadhaya Ajeet Rijal; Waha Andreas; Van Dooren Tom; Haass Christian; Birkenmeier Gerd; Pietrzik Claus U; Van Leuven Fred; Thal Dietmar Rudolf^*

来源：Journal of Neural Transmission, 2011, 118(5): 699-712.

DOI：10.1007/s00702-010-0572-7

• Alzheimer's disease
• Astrocytes
• Amyloid beta-protein
• Apolipoprotein E
• Perivascular space
• Neurons
• Blood-brain barrier

The deposition of amyloid-beta protein (A beta) in the brain is a hallmark of Alzheimer's disease (AD). Apolipoprotein E (apoE) is involved in the clearance of A beta from brain and the APOE epsilon 4 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 A beta. To further clarify the role of apoE in perivascular clearance of A beta, 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 A beta in the PVS. A beta and h-apoE were also found in the cytoplasm of perivascular astrocytes indicating that astrocytes take up the neuron-derived apoE bound to A beta, presumably prior to its clearance into the PVS. The uptake of apoE-A beta complexes into glial cells was further investigated in glioblastoma cells. It was mediated by alpha(2)macroglobulin receptor/low density lipoprotein receptor-related protein (LRP-1) and inhibited by adding receptor-associated protein (RAP). It results in endosomal A beta accumulation within these cells. These results suggest that neuronal apoE-A beta complexes, but not neuronal apoE alone, are substrates for LRP-1-mediated astroglial uptake, transcytosis, and subsequent perivascular drainage. Thus, the production of A beta and its interaction with apoE lead to the pathological perivascular drainage of neuronal apoE and provide insight into the pathological interactions of A beta with neuronal apoE metabolism.

• 出版日期2011-5