LRP/LR as an Alternative Promising Target in Therapy of Prion Diseases, Alzheimers Disease and Cancer

Abstract

The 37 kDa/67 kDa laminin receptor (LRP/LR) represents a key player for cell adhesion, is associated with the metastatic potential of solid tumors and is required for maintenance of cell viability by preventing apoptosis. LRP/LR acts as a receptor for viruses such as Sindbis virus, Venezuelean Equine Encephalitis (VEE) virus, Adeno-associated-viruses (AAV) and Dengue Virus, the latter causing 50 to 100 million infections in humans per year. LRP/LR acts further as a receptor for prions and represents a multifunctional protein subcellularly located to the nucleus, the cytoplasm and the cell surface. The receptor represents an alternative target for therapy of viral infections, cancer and prion disorders and might play additional roles in further neurodegenerative diseases such as Alzheimer's disease. The species barrier in prion disorders might be at least in part determined by the presence of LRP/LR in enterocytes of the intestinal epithelium. Anti-LRP/LR antibodies, siRNAs directed against LRP mRNA, polysulfated glycanes such as pentosan polysulfate and heparan mimetics and LRP decoy mutants are promising tools for blocking or downregulating the receptor and may represent alternative therapeutics for the treatment of prion disorders, Alzheimer's Disease and metastatic cancer.

Alimentary prion infections

“…15 However, prion intestinal translocation has been observed in the absence of M cells and has been demonstrated to be as a result of the action of polar, 37 kDa/67 kDa LRP/LR (non-integrin laminin receptor; reviewed in ref. [16][17][18] expressing enterocytes. Enterocytes are the major cell population of the intestinal epithelium and due to their ability to endocytose pathogens, nutrients and macromolecules, 19 it has been proposed that these cells may represent a major entry site for alimentary prions (Fig.…”

Advances in the development of antibody-based immunotherapy against prion disease

“…Recently, passive immunization has been extensively investigated ( Figure 1). 63,68,96,[108][109][110][111][112][113] Transgenic expression of the µ heavy chain of anti-PrP antibody 6H4 in PRNP -/-mice was found to completely prevent prion infection after intraperitoneal PrP Sc administration. 68 The most common way of administering anti-prion antibodies to prion-infected mice is peripherally.…”

“…The receptor represents an alternative target for the therapy of prion disorder and other neurodegenerative diseases. 113 "W3", a polyclonal antibody of LRP/LR, has abolished PrP Sc accumulation after incubation in cell-culture experiments. [131][132][133] In vivo experiments have also been undertaken in mice.…”

Retinoic-Acid-Induced Downregulation of the 67 KDa Laminin Receptor Correlates with Reduced Biological Aggressiveness of Human Neuroblastoma Cells

“…Among more than 60 genes identified, we could found LAMR1 (also called RPSA), encoding the precursor for the 67-KDa Laminin Receptor (67LR) (Wewer et al, 1986;Yow et al, 1988), whose mRNA levels were remarkably reduced after RA treatment. The 67LR is a multifunctional protein which is involved in cell adhesion, required for maintaining of cell viability (Scheiman et al, 2010;Susantad & Smith, 2008), acts as receptor for infectious agents like viruses and prions (Vana et al, 2009) and mediates the actions of the green tea polyphenol epigallocatechin-3-gallate (Umeda et al, 2008). Expression of 67LR has been www.intechopen.com correlated with the biological aggressiveness, and the invasive and metastatic capacities of tumors from diverse origin.…”