The core sequence of PIF competes for insulin/amyloid β in insulin degrading enzyme: potential treatment for Alzheimer’s disease

// Soren Hayrabedyan 1 , Krassimira Todorova 1 , Marialuigia Spinelli 2 , Eytan R. Barnea 3, 4, * and Martin Mueller 2, 5, 6, * 1 Institute of Biology and Immunology of Reproduction, Bulgarian Academy of Sciences, Laboratory of Reproductive OMICs Technologies, Sofia, Bulgaria 2 Department of Obstetrics and Gynecology, University Hospital Bern, University of Bern, Bern, Switzerland 3 Society for The Investigation of Early Pregnancy (SIEP), New York, NY, USA 4 BioIncept, New York, NY, USA 5 Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT, USA 6 Department of Paediatrics, School for Mental Health and Neuroscience, Maastricht University, Maastricht, The Netherlands * These authors have contributed equally to this work Correspondence to: Martin Mueller, email: martin.mueller@insel.ch Eytan R. Barnea, email: barnea@earlypregnancy.org Keywords: PreImplantation factor (PIF); Alzheimer’s disease; insulin degrading enzyme (IDE) Received: June 23, 2018      Accepted: August 16, 2018      Published: September 21, 2018 ABSTRACT The central pathological feature of Alzheimer’s disease (AD) is the sequential proteolytic processing of amyloid precursor protein (APP) to amyloid-β peptides (Aβ) agglomeration. The clearance of Aβ may be induced by the large zinc-binding protease insulin degrading enzyme (IDE). IDE is the common link between AD and Type II diabetes as insulin is an IDE target as well. Not surprisingly, the search for safe and effective drugs modulating IDE is ongoing. A new pregnancy derived peptide, PreImplantation Factor (PIF), inhibits neuro-inflammation and crosses the blood-brain-barrier. Importantly, we report that the (R 3 I 4 K 5 P 6 ) core sequence of the PIF peptide modulates IDE function and results in decreased Aβ agglomeration in neuronal cells. Using bioinformatics we show that PIF binds to the IDE complex and sterically competes for the same place as insulin or Aβ. The predicted RIKP sequence and especially the specific I 4 and P 6 amino acids are essential for hydrophobic interactions with the IDE complex. In terms of potential AD treatment, PIF was successfully tested in neurodegenerative animal models of perinatal brain injury and experimental autoimmune encephalitis. Importantly, sPIF received a FDA Fast Track Approval and orphan drug designation for first-in-human trial in autoimmunity.