Pentapeptide, targeting Serum Amyloid A and Amyloid β
suppresses /attenuates chronic inflammation, autoimmunity and neurodegeneration
Ma'ayan Shaked1 , Haim Ovadia2 , Keren-Or Amar1, Lora Eshkar –Sebban1 Shmuel Cohen1 , Michal Melamed1 , Jin Ryoun Kim 3 , Hanna Rosenmann4 ,Mary Cowman5, Ehud Cohen6 and David Naor1
1The Lautenberg Center of Immunology and Cancer Research ,Faculty of Medicine, Hebrew University of Jerusalem, Israel; 2Department of Neurology, Hadassah-Hebrew University Medical Center , Jerusalem ,Israel; 3Othmer-Jacobs Department of Chemical and Biological Engineering, Polytechnic Institute of New York University, Brooklyn, USA; 4Department of Neurology,The Agnes Ginges Center for Human Neurogenetics, Hadassah-Hebrew University Medical Center; 5Tandon School of Engineering, New York University, New York, NY, USA, 6Department of Biochemistry and Molecular Biology, Institute for Medical Research Israel–Canada, Hebrew University, School of Medicine, Jerusalem, Israel;
5-mer peptide (MTADV-Methionin, Threonine, Alanine, Aspartic acid, Valine) was derived from a pro-inflammatory CD44 variant that expressed mostly, if not exclusively, in inflamed joints of a rheumatoid arthritis (RA) patient. The 5-MER MTADV is acetylated-N amidated-C to improve its stability. The MTADV interacting with the amyloid proteins, Serum Amyloid A (SAA), transthyretin and Apolipoprotein B, prevents/attenuates aggregation or polymerization of pathological amyloid proteins (SAA, Transthyretin). In addition, preliminary evidence revealed that it can also target Amyloid β. The MTADV peptide is polymerized in solution, displays β sheet configuration with alternating hydrophobic-hydrophilic amino acids, can cross cell membrane and lost its activity after amino acid scrambling. The 5-mer peptide exhibits therapeutic activity in mouse models of inflammatory diseases associated with the stress acute phase protein SAA, such as RA, inflammatory bowel disease (IBD) and multiple sclerosis (MS). For example, daily oral delivery of the MTADV peptide, starting 5 days after induction Experimental Autoimmune Encephalomyelitis (EAE) by MOG, attenuated limb paralysis in mouse model of MS. This finding further indicates that the peptide can tolerate the digestive system. The 5-mer peptide does not interfere with normal immune responses, such as delayed type hypersensitivity and does not generate, as expected, neutralizing antibodies after IP injection. C. elegans worms, expressing human Amyloid β transgene, which induces muscle paralysis, restore their movement potential after "feeding" with MTADV. Finally, a preliminary experiment reveals that Alzheimer's -like mice (5XFAD transgenic mice)-restored their learning potential after daily IP injection with MTADV peptide. To this end, Alzheimer's 5x FAD-transgenic mice treated with MTADV showed the same learning potential as wild type mice, whereas the Alzheimer's mice, that were not treated with the peptide display learning difficulties. Can the peptide therapeutic effects proven in animal model, be clinically translated? This question the focus of our current studies.