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

Hayrabedyan, Soren; Todorova, Krassimira; Spinelli, Marialuigia; Barnea, Eytan R; Müller, Martin (2018). The core sequence of PIF competes for insulin/amyloid β in insulin degrading enzyme: potential treatment for Alzheimer's disease. OncoTarget, 9(74), pp. 33884-33895. Impact Journals LLC 10.18632/oncotarget.26057

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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 (RIKP) 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 and P 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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Department of Gynaecology, Paediatrics and Endocrinology (DFKE) > Clinic of Gynaecology

UniBE Contributor:

Spinelli, Marialuigia and Müller, Martin

Subjects:

600 Technology > 610 Medicine & health

ISSN:

1949-2553

Publisher:

Impact Journals LLC

Language:

English

Submitter:

Monika Zehr

Date Deposited:

03 Apr 2019 12:35

Last Modified:

26 Oct 2019 01:54

Publisher DOI:

10.18632/oncotarget.26057

PubMed ID:

30338033

Uncontrolled Keywords:

Alzheimer's disease PreImplantation factor (PIF) insulin degrading enzyme (IDE)

BORIS DOI:

10.7892/boris.125874

URI:

https://boris.unibe.ch/id/eprint/125874

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