Prolyl Oligopeptidase: A Rising Star on the Stage of Neuroinflammation Research

Abstract

Inhibitors of prolyl oligopeptidase have been reported to be neuroprotective, especially in memory loss caused by lesion or disease. This enzyme has also been implicated in neurodegeneration. Although it was initially thought that prolyl oligopeptidase functioned to directly control of neuropeptide levels, emerging evidence points out in part that this peptidase modulates peptides which in turn regulate inflammatory responses. Here we review the recent literature which indicates a direct involvement of prolyl oligopeptidase in several inflammatory diseases. Neuroinflammation generates neurotoxins with a relevant role in neurodegenerative diseases, and it is within this toxin generation where prolyl oligopeptidase might have a role.

The role of Thyrotropin Releasing Hormone in aging and neurodegenerative diseases

“…The potential actions of POP in AD may not though be solely limited to modifying TRH processing as POP also plays a role in hydrolyzing several other peptides and hormones, many of which are affected in AD and neuroinflammatory conditions (Penttinen et al, 2011). For example, alterations consistent with inflammation have been observed in microglia and astrocytes surrounding senile plaques, in addition to the presence of proinflammatory markers and elevated chemokines and cytokines surrounding these plaques (Glass et al 2010).…”

Translational research on prolyl oligopeptidase inhibitors: the long road ahead

“…The hypothesis underlying the mode of action, that is, increasing the active life of certain neuropeptides, did not presume to modify the underlying causes of neurodegeneration [5]. Research in the new millennium, however, produced new hypotheses about the role of PREP in signaling, intracellular trafficking and secretion, synaptic neurotransmission, development, aging, inflammation and formation of neurotoxic protein aggregates [6][7][8][9][10][11]. This is also reflected in the claims made in the new patents that are much broader than anti-amnesic and cognition enhancing, targeting neurodegeneration, brain damage and inflammation.…”

“…First, PREP inhibitors reduce the number of cells with a-synuclein aggregates in a cellular model of Parkinson's disease [8]. A second observation is that PREP appears to be involved in the in vivo generation of immunoactive peptides, ac-PGP, from collagen, and the tetrapeptide ac-SDKP from a precursor derived from thymosin-b4 (reviewed in [11]). The first one stimulates immunoactive cells, and the second has anti-inflammatory properties.…”

Prolyl endopeptidase is involved in the degradation of neural cell adhesion molecules in vitro

“…Besides its extracellular action, PREP has been shown to act intracellularly and important roles of PREP have been demonstrated in signaling pathways or in transport and secretion of proteins and peptides associated with neurodegeneration (Brandt et al, 2008;Di Daniel et al, 2009;Rossner et al, 2005;Savolainen et al, 2015;Schulz et al, 2002Schulz et al, , 2005. Within recent years PREP has been suggested to be a contributor to neuroinflammation (Penttinen et al, 2011). PREP has been shown to be involved in mechanisms responsible for the transduction and amplification of inflammatory processes leading to the production of neurotoxic mediators, which in turn mediate pathology progression (for review, see Penttinen et al, 2011).…”

“…Within recent years PREP has been suggested to be a contributor to neuroinflammation (Penttinen et al, 2011). PREP has been shown to be involved in mechanisms responsible for the transduction and amplification of inflammatory processes leading to the production of neurotoxic mediators, which in turn mediate pathology progression (for review, see Penttinen et al, 2011).…”