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

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 (R3I4K5P6) 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 I4 and P6 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.

Current Understanding of the Physiopathology, Diagnosis and Therapeutic Approach to Alzheimer’s Disease

“…This fact would cause, secondarily, the accumulation of both peptides at the brain level [ 56 ]. Stimulation of the production of the insulin-degrading enzyme decreases the levels of Aβ and the formation of SP [ 57 ] which could be used as a therapeutic alternative in the treatment of AD.…”

Blue autofluorescence in protein aggregates “lighted on” by UV induced oxidation

“…Ubiquitin from bovine erythrocytes, recombinant Human Insulin and Thioflavin T were purchased from Sigma Aldrich and used without further purification. Aβ(1-40) was purchased from Biopeptide and pre-treated as previously reported 64 .…”

Preimplantation factor modulates oligodendrocytes by H19-induced demethylation of NCOR2

“…It is conceivable that cofactors of sPIF likely act in concert to elicit downstream effects that are specific to sPIF but different depending on the maturation stage of the brain. Identification of PIF-interacting cofactors is currently underway as in the case of insulin-degrading enzyme in Alzheimer disease ( 55 ). The exact mechanisms of how sPIF interacts with the cell to induce differentiation (upstream of H19 ) has not been addressed yet but is beyond the scope of this manuscript.…”