Deficiency of prolyl oligopeptidase in mice disturbs synaptic plasticity and reduces anxiety-like behaviour, body weight, and brain volume

Höfling, Corinna; Kulesskaya, Natalia; Jaako, Külli; Peltonen, Iida; Männistö, Pekka T.; Nurmi, Antti; Vartiainen, Nina; Morawski, Markus; Zharkovsky, Alexander; Võikar, Vootele; Rößner, Steffen; Garcı́a-Horsman, J. Arturo

doi:10.1016/j.euroneuro.2016.02.015

Cited by 28 publications

(33 citation statements)

References 55 publications

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“…Immunohistochemistry for CD‐45 or Iba‐1 was performed by protocol described previously . In brief, free‐floating serial sections throughout the hippocampus (each 20th section; 800 μm apart) were incubated in 0.3% H 2 O 2 in PBS followed by 0.01 m citrate buffer (pH = 6.0) incubation.…”

Section: Methodsmentioning

confidence: 99%

Effects of the drug combination memantine and melatonin on impaired memory and brain neuronal deficits in an amyloid-predominant mouse model of Alzheimer's disease

Jürgenson

Zharkovskaja

Noortoots

et al. 2019

Journal of Pharmacy and Pharmacology

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Objectives Alzheimer's disease (AD) is a neurodegenerative disorder with no cure. Limited treatment options available today do not offer solutions to slow or stop any of the suspected causes. The current medications used for the symptomatic treatment of AD include memantine and acetylcholine esterase inhibitors. Some studies suggest that melatonin could also be used in AD patients due to its sleep‐improving properties. Methods In this study, we evaluated whether a combination of memantine with melatonin, administered for 32 days in drinking water, was more effective than either drug alone with respect to Aβ aggregates, neuroinflammation and cognition in the double transgenic APP/PS1 (5xFAD) mouse model of AD. Key findings In this study, chronic administration of memantine with melatonin improved episodic memory in the object recognition test and reduced the number of amyloid aggregates and reactive microgliosis in the brains of 5xFAD mice. Although administration of memantine or melatonin alone also reduced the number of amyloid aggregates and inflammation in brain, this study shows a clear benefit of the drug combination, which had a significantly stronger effect in this amyloid‐dominant mouse model of AD. Conclusion Our data suggest considerable potential for the use of memantine with melatonin in patients with AD.

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Section: Methodsmentioning

confidence: 99%

Effects of the drug combination memantine and melatonin on impaired memory and brain neuronal deficits in an amyloid-predominant mouse model of Alzheimer's disease

Jürgenson

Zharkovskaja

Noortoots

et al. 2019

Journal of Pharmacy and Pharmacology

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“…The expression of PREP protein in mouse brain has been demonstrated to be elevated in microglial cells and astrocytes after an inflammatory insult . Furthermore, PREP knockout mice were resistant to the microglia‐activating effect of lipopolysaccharide (LPS) treatment . Brain PREP levels were significantly elevated in an in vivo rat model of neuroinflammation, and notably, in rats experiencing neuroinflammation, a microdialysis approach revealed increased PREP activity in the brain extracellular space, although under normal conditions, the enzyme is known to be mainly cytosolic .…”

Section: Introductionmentioning

confidence: 99%

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

Natunen

Gynther

Rostalski

et al. 2018

Basic Clin Pharma Tox

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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 toxicity and reduced the levels of the pro-inflammatory cytokine tumour necrosis factor alpha. In conclusion, these data point to an extracellular role for microglial PREP in the inflammatory process. Inhibition of PREP during neuroinflammation is a potential target for neuroprotection. Thus, PREP inhibitors may offer a novel therapeutic approach for the treatment of neurodegenerative disorders with an inflammatory component including Parkinson's and Alzheimer's diseases.

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“…In humans, even though it is present in many different cell types, current investigations are highly focused on the roles of PREP in the brain 2, 3 . In addition to its enzymatic function, these studies and others support the hypothesis that PREP might be involved in neurogenesis, hippocampal plasticity and spatial memory formation both in healthy and diseased states 2, 3 . Protein-protein interactions rather than proteolytic activity seem to underlie the actions of PREP in synaptic plasticity 4–6 .…”

Section: Introductionmentioning

confidence: 99%

Dynamics and ligand-induced conformational changes in human prolyl oligopeptidase analyzed by hydrogen/deuterium exchange mass spectrometry

Tsirigotaki

Elzen

Veken

et al. 2017

Sci Rep

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Prolyl oligopeptidase (PREP) is conserved in many organisms across life. It is involved in numerous processes including brain function and neuropathology, that require more than its strict proteolytic role. It consists of a seven-bladed β-propeller juxtaposed to a catalytic α/β-hydrolase domain. The conformational dynamics of PREP involved in domain motions and the gating mechanism that allows substrate accessibility remain elusive. Here we used Hydrogen Deuterium eXchange Mass Spectrometry (HDX-MS) to derive the first near-residue resolution analysis of global PREP dynamics in the presence or absence of inhibitor bound in the active site. Clear roles are revealed for parts that would be critical for the activation mechanism. In the free state, the inter-domain interface is loose, providing access to the catalytic site. Inhibitor binding “locks” the two domains together exploiting prominent interactions between the loop of the first β-propeller blade and its proximal helix from the α/β-hydrolase domain. Loop A, thought to drive gating, is partially stabilized but remains flexible and dynamic. These findings provide a conformational guide for further dissection of the gating mechanism of PREP, that would impact drug development. Moreover, they offer a structural framework against which to study proteolysis-independent interactions with disordered proteins like α-synuclein involved in neurodegenerative disease.

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Deficiency of prolyl oligopeptidase in mice disturbs synaptic plasticity and reduces anxiety-like behaviour, body weight, and brain volume

Cited by 28 publications

References 55 publications

Effects of the drug combination memantine and melatonin on impaired memory and brain neuronal deficits in an amyloid-predominant mouse model of Alzheimer's disease

Effects of the drug combination memantine and melatonin on impaired memory and brain neuronal deficits in an amyloid-predominant mouse model of Alzheimer's disease

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

Dynamics and ligand-induced conformational changes in human prolyl oligopeptidase analyzed by hydrogen/deuterium exchange mass spectrometry

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