Extracellular prolyl oligopeptidase derived from activated microglia is a potential neuroprotection target

Basic & Clinical Pharmacology & Toxicology
Teemu A NatunenAaro J Jalkanen

Abstract

Prolyl oligopeptidase (PREP) is an abundant peptidase in the brain and periphery, but its physiological functions are still largely unknown. Recent findings point to a role for PREP in inflammatory processes. This study assessed the cellular and extracellular PREP activities in cultures of mouse primary cortical neurons, microglial cells and astrocytes, and immortalized microglial BV-2 cells under neuroinflammatory conditions induced by lipopolysaccharide (LPS) and interferon gamma (IFNγ). Furthermore, we evaluated the neuroprotective effect of a specific PREP inhibitor, KYP-2047, in a neuroinflammation model based on a coculture of primary cortical neurons and activated BV-2 cells. The inflammatory insult reduced intracellular and increased extracellular PREP activity specifically in microglial cells, suggesting that activated microglia excretes active PREP. A targeted proteomics approach revealed up-regulation in PREP protein levels in BV-2 cell growth medium but down-regulation in crude membrane-bound PREP after LPS+IFNγ. In the coculture of BV-2 cells and primary neurons, an increase in extracellular PREP activity was also detected after inflammation. KYP-2047 (10 μmol/L) significantly protected neurons against microglial t...Continue Reading

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Citations

Nov 11, 2020·Molecular Neurodegeneration·Teemu NatunenMikko Hiltunen
Dec 4, 2019·Neuroscience and Biobehavioral Reviews·Benjamín RodríguezMirian A F Hayashi
May 21, 2020·Biochimica Et Biophysica Acta. General Subjects·Yakov E DunaevskyElena N Elpidina
Jun 30, 2021·Neurochemistry International·Ivan A LindhoutAndis Klegeris
Sep 7, 2021·Journal of Cellular and Molecular Medicine·Hengjing CuiTimo T Myöhänen

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