Localization of the alpha 2 macroglobulin receptor (alpha 2MR) was studied in postmortem human brain tissue of Alzheimer disease (AD) and age-matched control cases with a monoclonal antibody (A2MR alpha 2) to the receptor. In control cases alpha 2MR was detected in neurons, glia, and some capillaries. Neuronal staining was most conspicuous in the hippocampus and entorhinal cortex. In AD, alpha 2MR immunoreactivity was enhanced. The staining intensity of some neurons was increased, as was the number of positive glial cells. In addition, senile plaques, tangles, and dystrophic neurites were strongly stained. These results suggest that alpha 2MR is involved in AD pathology.

Aged↗

PubMedDate not supplied

Receptors for alpha 2-macroglobulin- and pregnancy zone protein-proteinase complexes in the human placental syncytiotrophoblast.

Receptors for complexes between alpha 2-macroglobulin (alpha 2M) and proteinases (e.g. trypsin) were identified and characterized in the human placenta. The receptors also bound the complex formed between pregnancy zone protein (PZP) and chymotrypsin, although with slightly lower affinity, whereas binding of alpha 2M or PZP in their native forms was negligible. Treatment with methylamine to cleave the internal thiol esters caused an increase in binding affinity of alpha 2M to the level of alpha 2M-trypsin but only a minor increase in the affinity of PZP. Chorionic villi prepared from normal full-term placentae were approximately half occupied by endogenous alpha 2M or PZP complexes. These ligands, as well as prebound 125I-labelled alpha 2M-trypsin, were rapidly removed by the addition of 5 mM EDTA. Binding was similar in villi from eight-week and full-term placentae. Autoradiography showed that labelled alpha 2M-trypsin was associated with the syncytiotrophoblast. The kinetics of 125I-labelled alpha 2M-trypsin binding at 4 degrees C was similar in isolated villi and microvillous membranes. Association was slow, with apparent equilibrium by about 16 h. Dissociation of prebound tracer was slow but markedly accelerated in the presence of unlabelled ligand at a saturating concentration. The concentration-dependence of binding at equilibrium yielded a non-linear Scatchard plot. Most of the binding of ligand at tracer concentration was accounted for by high-affinity receptors with a dissociation constant (Kd) of about 50 pM. The content of high-affinity receptors in one placenta was estimated as approximately 125 pmol, i.e., a significant fraction of the total receptor population in the pregnant woman.

Chorionic Villi↗

PubMedDate not supplied

The biologic potency and binding affinity of biosynthetic human insulin in isolated rat adipocytes.

Using the isolated rat adipocyte system, we could not detect any difference in binding affinity or biologic potency of biosynthetic and pancreatic human insulin.

Adipose Tissue↗

PubMedDate not supplied

Low alpha 2-macroglobulin-proteinase complex binding: a common but not exclusive characteristic of malignant cells.

125I-labelled alpha 2-macroglobulin complexed with trypsin bound to human cancer cell lines (HTB 144, CRL 1427, CCL 30, HB 8065, CCL 2, CRL 1593) but to a lesser degree than to normal cells. Malignant transformation of murine BALB/c 3T3 cells with Kirsten sarcoma virus caused a 50% reduction in the alpha 2-macroglobulin-trypsin complex binding. Two cloned revertants derived from the malignant BALB/c 3T3 cells did not induce tumors upon syngrafting. One exhibited normal binding and the other reduced binding. A reduced alpha 2M-proteinase complex binding is thus common in tumor cells but is not a unique property of the malignant state.

Biomarkers, Tumor↗

PubMedDate not supplied

Receptors of the low density lipoprotein (LDL) receptor family in man. Multiple functions of the large family members via interaction with complex ligands.

The LDL receptor family members are endocytic receptors composed of repeated protein modules, including clusters of ligand binding LDL receptor class A (LA) repeats. The large (approximately 600 kDa) members LRP and megalin bind numerous structurally unrelated and often complex ligands at different combinations of sites. LRP is expressed in a wide but restricted set of cell types including hepatocytes, macrophages, smooth muscle cells, and neurons of the CNS. Megalin is expressed in various epithelia including proximal kidney tubules, intestine, and ependymal cells. The two receptors share a multitude of ligands, and their function in vivo is therefore to a large extent determined by their expression pattern. For example, both receptors can endocytose lipoproteins, but this function appears mainly relevant for LRP. In addition, LRP helps regulating urokinase receptor expression on the cell surface via ligand-mediated internalization followed by return of the naked urokinase receptor to the cell surface. Both receptors also have specialist functions. LRP is specific for binding of alpha2-macroglobulin-proteinase complexes and provides clearance of the complexes and of peptides, e.g. cytokines, associated with the complex. Megalin has important functions in vitamin B12 homeostasis since it specifically mediates uptake of the vitamin B12-transcobalamin complex and helps building a storage pool for the vitamin in the kidneys. Moreover, megalin binds cubilin, the recently identified receptor for B12-intrinsic factor complex, thus providing a mechanism for uptake of dietary vitamin B12. Finally, megalin specifically mediates uptake of apolipoprotein J/clusterin, a binding protein for the Abeta peptide implicated in Alzheimer's disease. The binding of multiple complex ligands that belong to distinct physiological systems provides a challenge in future studies aiming at elucidating the role of LRP and megalin in disease mechanisms.

Humans↗