Brain prolyl oligopeptidase activity is associated with neuronal damage rather than β-amyloid accumulation

Laitinen, Kirsti; Groen, Thomas van; Tanila, Heikki; Venäläinen, Jarkko I.; Männistö, Pekka T.; Alafuzoff, Irina

doi:10.1097/00001756-200110290-00032

Cited by 28 publications

(23 citation statements)

References 17 publications

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“…Of course, based on these observations, it is not possible to state whether the increased PEP expression by individual neurons contributes to AD pathology. However, the neuroprotective effects of PEP inhibition on one side and the frequent co-occurance of robust PEP expression and morphological characeristics of neurodegeneration in the AD brain on the other side indicate that increased PEP expression may play a role in ADassociated neurodengeration as also suggested in by Laitinen et al (20). The brains of AD patients are also characterized by a robust activation of microglial cells and astrocytes in proximity to b-amyloid plaques.…”

Section: Pep Expression In Human Brainmentioning

confidence: 77%

Brain Prolyl Endopeptidase Expression in Aging, APP Transgenic Mice and Alzheimer’s Disease

et al. 2005

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Prolyl endopeptidase (PEP) is believed to inactivate neuropeptides that are present in the extracellular space. However, the intracellular localization of PEP suggests additional, yet unidentified physiological functions for this enzyme. Here we studied the expression, enzymatic activity and subcellular localization of PEP in adult and aged mouse brain as well as in brains of age-matched APP transgenic Tg2576 mice and in brains of Alzheimer's disease patients. In mouse brain PEP was exclusively expressed by neurons and displayed region- and age-specific differences in expression levels, with the highest PEP activity being present in cerebellum and a significant increase in hippocampal but not cortical or cerebellar PEP activity in aged mouse brain. In brains of young APP transgenic Tg2576 mice, hippocampal PEP activity was increased compared to wild-type littermates in the pre-plaque phase but not in aged mice with beta-amyloid plaque pathology. This "accelerated aging" with regard to hippocampal PEP expression in young APP transgenic mice might be one factor contributing to the observed cognitive deficits in these mice in the pre-plaque phase and could also explain in part the cognition-enhancing effects of PEP inhibitors in several experimental paradigms.

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Section: Pep Expression In Human Brainmentioning

confidence: 77%

Brain Prolyl Endopeptidase Expression in Aging, APP Transgenic Mice and Alzheimer’s Disease

et al. 2005

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“…Since many of these neuropeptides are connected with learning and memory functions [11,12], and also with neurodegenerative disorders such as Parkinson’s and Alzheimer’s diseases [11], POP has been considered as a target for treatment of different neuropsychiatric and cognitive disorders [13,14]. It has been suggested that POP plays a role in aging processes since its activity has been reported to be associated with neuronal degeneration [15,16]. In addition, alterations in enzymatic activities of plasma POP have been measured in many different psychiatric conditions [17,18] and in Parkinson’s and Alzheimer’s diseases [19].…”

Section: Introductionmentioning

confidence: 99%

Sequential Expression, Activity and Nuclear Localization of Prolyl Oligopeptidase Protein in the Developing Rat Brain

Hannula¹,

Männistö²,

Myöhänen³

2010

Dev Neurosci

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Prolyl oligopeptidase (POP) is a serine protease that hydrolyzes peptides shorter than 30-mer. Some evidence has recently been obtained that POP can generate protein-protein interactions and therefore participate in various physiological and pathological events. Several studies have reported that POP may be involved in neurogenesis since its activity increases during development and can be found in the nucleus of proliferating tissues. In cell cultures, POP has been shown to be localized in the nucleus, but only early in the development, since during maturation it is moved to the cytosol. We have now studied for the first time the expression of POP protein, its enzymatic activity and nuclear localization in vivo in the developing rat brain. We observed that enzymatic activity of POP is highest on embryonic day 18 while the protein amounts reach their peak at birth. Furthermore, POP is located in the nucleus only early in the development but is transferred to the cytosol already before parturition. Our in vivo results confirm the previous cell culture results supporting the role of POP in neurogenesis. A discordance of antenatal protein amounts and enzymatic activities is suggesting a tight regulation of POP activity and possibly even a nonhydrolytic role at that stage.

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“…It is believed to act both extracellularly, where it is involved in the maturation and degradation of peptide hormones and neuropeptides, including substance P and neurotensin (Bellemere et al, 2004;Cunningham and O'Connor, 1997), and intracellularly where it may be part of signaling pathways or contribute to transport and secretion of proteins and peptides including Alzheimer amyloid beta (Ab) protein Schulz et al, 2002Schulz et al, , 2005. It has been speculated that PEP may play a role in the pathogenesis of AD based on studies showing abnormal expression of this enzyme in brain samples from AD patients and in transgenic mice overexpressing Alzheimer amyloid precursor protein (APP) (Cunningham and O'Connor, 1997;Laitinen et al, 2001;Rossner et al, 2005). PEP inhibitors have also been shown to have neuroprotective and memory-enhancing effects that have been attributed to their ability to modify neuropeptide metabolism (Cunningham and O'Connor, 1997;Makinen et al, 1994).…”

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confidence: 99%

Prolyl endopeptidase is revealed following SILAC analysis to be a novel mediator of human microglial and THP‐1 cell neurotoxicity

Klegeris

Bammler

et al. 2008

Glia

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Reactive microglial cells may exacerbate the pathology in some neurodegenerative disorders. Supernatants of stimulated human microglial cells, or their surrogate THP-1 cells, are lethal to cultured human neuroblastoma SH-SY5Y cells. To explore this neurotoxicity, we examined the spectrum of proteins generated by THP-1 cells using the technique of stable isotope labeling by amino acids in cell culture (SILAC). Unstimulated cells were grown in medium with light L-[(12)C(6)] arginine while cells stimulated by lipopolysaccharide (LPS) plus interferon-gamma (IFN-gamma) were grown in medium with heavy L-[(13)C(6)] arginine. Proteins isolated from the media were digested with trypsin, and relative concentrations of generated peptides determined by mass spectrometry. More than 1,500 proteins or putative proteins were identified. Of these, 174 were increased and 189 decreased by more than twofold in the stimulated cell supernatant. We selected one upregulated protein, prolyl endopeptidase (PEP), for further investigation of its potential contribution to neurotoxicity. We first confirmed its upregulation by comparing its enzymatic activity in stimulated and unstimulated cell supernatants. We then evaluated two specific PEP inhibitors, Boc-Asn-Phe-Pro-aldehyde and Z-Pro-Pro-aldehyde-dimethyl acetal, for their potential to reduce toxicity of stimulated THP-1 cell and human microglia supernatants towards SH-SY5Y cells. We found both to be partially protective in a concentration-dependent manner. Inhibition of PEP may be a therapeutic approach to neurodegenerative disorders including Alzheimer and Parkinson diseases.

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Brain prolyl oligopeptidase activity is associated with neuronal damage rather than β-amyloid accumulation

Cited by 28 publications

References 17 publications

Brain Prolyl Endopeptidase Expression in Aging, APP Transgenic Mice and Alzheimer’s Disease

Brain Prolyl Endopeptidase Expression in Aging, APP Transgenic Mice and Alzheimer’s Disease

Sequential Expression, Activity and Nuclear Localization of Prolyl Oligopeptidase Protein in the Developing Rat Brain

Prolyl endopeptidase is revealed following SILAC analysis to be a novel mediator of human microglial and THP‐1 cell neurotoxicity

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