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

The deposition of amyloid-ß protein (Aß) in the brain is a hallmark of Alzheimer's disease (AD). Apolipoprotein E (apoE) is involved in the clearance of Aß 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 Aß. To further clarify the role of apoE in perivascular clearance of Aß, 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 Aß in the PVS. Aß and h-apoE were also found in the cytoplasm of perivascular astrocytes indicating that astrocytes take up the neuron-derived apoE bound to Aß, presumably prior to its clearance into the PVS. The uptake of apoE-Aß 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 Aß accumulation within these cells. These results suggest that neuronal apoE-Aß complexes, but not neuronal apoE alone, are substrates for LRP-1-mediated astroglial uptake, transcytosis, and subsequent perivascular drainage. Thus, the production of Aß and its interaction with apoE lead to the pathological perivascular drainage of neuronal apoE and provide insight into the pathological interactions of Aß with neuronal apoE metabolism.

Wnt5a/Ror2-induced upregulation of xPAPC requires xShcA.

Ror receptor-tyrosine kinases act as Wnt-5a receptors in beta-catenin independent Wnt-signaling pathways. In Xenopus, expression of xPAPC is regulated by a Wnt-5a/Ror2 pathway, which resembles typical signaling cascades downstream of receptor-tyrosine kinases. Here, we have identified the phospho-tyrosine binding protein ShcA as an intracellular binding partner of Ror2. ShcA binds to a conserved motif in Ror2 via its SH2-domain. Wnt-5a induces clustering of Ror2 in the cell membrane and recruitment of ShcA to the Ror2 receptor complex. We further show that ShcA is co-expressed with Ror2 in developing Xenopus embryos and ShcA is required for Wnt-5a/Ror2 mediated upregulation of xPAPC, demonstrating the functional relevance of this interaction.