Abstract
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 β-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 serveral experimental paradigms.
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Abbreviations
- AD:
-
Alzheimer’s disease
- APP:
-
amyloid precursor protein
- bio-GSA:
-
biotinylated lectin from Griffonia simplicifolia agglutinin (isolectin B4)
- GFAP:
-
glial fibrillary acidic protein
- HEPES:
-
4-(2-hydroxyethyl)piperazine-1-ethanesulfonic acid
- PB:
-
phosphate buffer
- PBS:
-
phosphate-buffered saline
- PEP:
-
prolyl endopeptidase (EC 3.4.21.26)
References
F. Goossens I. Meester ParticleDe G. Vanhoof S. Scharpe (1996) ArticleTitleDistribution of prolyl oligopeptidase in human peripheral tissues and body fluids Eur. J. Clin. Chem. Clin. Biochem. 34 17–22 Occurrence Handle8704029
R. Mentlein (1988) ArticleTitleProline residues in the maturation and degradation of peptide hormones and neuropeptides FEBS Lett. 234 251–256 Occurrence Handle10.1016/0014-5793(88)80092-9 Occurrence Handle3292288
S. Wilk (1983) ArticleTitleProlyl endopeptidase Life Sci. 33 2149–2157 Occurrence Handle10.1016/0024-3205(83)90285-0 Occurrence Handle6358755
K. Dresdner L. A. Barker M. Orlowski S. Wilk (1982) ArticleTitleSubcellular distribution of prolyl endopeptidase and cation-sensitive neutral endopeptidase in rabbit brain J. Neurochem. 38 1151–1154 Occurrence Handle7038048
Schulz, I., Zeitschel, U., Rudolph, T., Gerhartz, B., Bigl, V., Demuth, H.-U., and Roßner, S. 2005. Subcellular localization suggests novel functions for prolyl endopeptidase in protein secretion. J. Neurochem. 94:970–979.
S. Roßner U. Ueberham R. Schliebs J. R. Perez-Polo V. Bigl (1998) ArticleTitleThe regulation of APP metabolism by cholinergic mechanisms and neurotrophin receptor signaling Progr. Neurobiol. 56 541–569 Occurrence Handle10.1016/S0301-0082(98)00044-6 Occurrence Handle9775403
D. J. Selkoe D. Schenk (2003) ArticleTitleAlzheimer’s disease: molecular understanding predicts amyloid-based therapeutics Annu. Rev. Pharmacol. Toxicol. 43 545–584 Occurrence Handle10.1146/annurev.pharmtox.43.100901.140248 Occurrence Handle12415125
Schulz, I., Rosche, F., Manhart, S., Rahfeld, J.-U., Heiser, U., Hoffmann, T., Wermann, M., Bär, J., and Demuth, H.-U. 2005. NPXY-motif containing C-terminal C31 fragment of amyloid precursor protein – A putative novel intracellular substrate of prolyl endopeptidase. Submitted.
S. Soriano D. C. Lu S. Chandra C. U. Pietrzik E. H. Koo (2001) ArticleTitleThe amyloidogenic pathway of amyloid precursor protein (APP) is independent of its cleavage by caspases J. Biol. Chem. 276 29045–29050 Occurrence Handle10.1074/jbc.M102456200 Occurrence Handle11397796
K. Hsiao P. Chapman S. Nilsen C. Eckman Y. Harigaya S. Younkin F. Yang G. Cole (1996) ArticleTitleCorrelative memory deficits, Aβ elevation and amyloid plaques in transgenic mice Science 274 99–102 Occurrence Handle8810256
G. McKhann D. Drachmann M. Folstein R. Katzman D. Price E. M. Stadlan (1984) ArticleTitleClinical diagnosis of Alzheimer’s disease: Report of the NINCDS-ADRDA work group under the auspices of Department of Health and Human Services Task Force on Alzheimer’s disease Neurology 34 939–944 Occurrence Handle6610841
I. Schulz B. Gerhartz A. Neubauer A. Holloschi U. Heiser M. Hafner H. U. Demuth (2002) ArticleTitleModulation of inositol 1,4,5-triphosphate concentration by prolyl endopeptidase inhibition Eur. J. Biochem. 269 5813–5820 Occurrence Handle10.1046/j.1432-1033.2002.03297.x Occurrence Handle12444969
C. H. Jiang J. Z. Tsien P. G. Schultz Y. Hu (2001) ArticleTitleThe effects of aging on gene expression in the hypothalamus and cortex of mice Proc. Natl. Acad. Sci. USA 98 1930–1934 Occurrence Handle10.1073/pnas.98.4.1930 Occurrence Handle11172053
K. Toide Y. Iwamoto T. Fujiwara H. Abe (1995) ArticleTitleJTP-4819: A novel prolyl endopeptidase inhibitor with potential as a cognitive enhancer J. Pharmacol. Exp. Ther. 274 1370–1378 Occurrence Handle7562510
M. Shinoda A. Matsuo K. Toide (1996) ArticleTitlePharmacological studies of a novel prolyl endopeptidase inhibitor, JTP-4819, in rats with middle cerebral artery occlusion Eur. J. Pharmacol. 305 31–38 Occurrence Handle10.1016/0014-2999(96)00173-2 Occurrence Handle8813528
Y. Shishido M. Furushiro S. Tanabe S. Shibata S. Hashimoto T. Yokokura (1999) ArticleTitleEffects of prolyl endopeptidase inhibitors and neuropeptides on delayed neuronal death in rats Eur. J. Pharmacol. 372 135–142 Occurrence Handle10.1016/S0014-2999(99)00185-5 Occurrence Handle10395093
W. C. Benzing J. R. Wujek E. K. Ward D. Shaffer K. H. Ashe S. G. Younkin K. R. Brunden (1999) ArticleTitleEvidence for glial-mediated inflammation in aged APPsw transgenic mice Neurobiol. Aging 20 581–589 Occurrence Handle10.1016/S0197-4580(99)00065-2 Occurrence Handle10674423
G. Mehlhorn M. Hollborn R. Schliebs (2000) ArticleTitleInduction of cytokines in glial cells surrounding cortical β-amyloid plaques in transgenic Tg2576 mice with Alzheimer pathology Int. J. Devl. Neurosci. 18 423–431 Occurrence Handle10.1016/S0736-5748(00)00012-5
J. Apelt R. Schliebs (2001) ArticleTitleβ-Amyloid-induced glial expression of both pro-and anti-inflammatory cytokines in cerebral cortex of aged transgenic Tg2576 mice with Alzheimer plaque pathology Brain Res. 894 21–30 Occurrence Handle10.1016/S0006-8993(00)03176-0 Occurrence Handle11245811
K. S. Laitinen T. Groen Particlevan H. Tanila J. Venalainen P. T. Mannisto I. Alafuzoff (2001) ArticleTitleBrain prolyl oligopeptidase activity is associated with neuronal damage rather than beta-amyloid accumulation Neuroreport 12 3309–3312 Occurrence Handle10.1097/00001756-200110290-00032 Occurrence Handle11711876
L. Holcomb M. N. Gordon E. McGowan X. Yu S. Benkovic P. Jantzen K. Wright I. Saad R. Mueller D. Morgan S. Sanders C. Zehr K. O’Campo J. Hardy C. M. Prada C. Eckman S. Younkin K. Hsiao K. Duff (1998) ArticleTitleAccelerated Alzheimer-type phenotype in transgenic mice carrying both mutant amyloid precursor protein and presenilin 1 transgenes Nat. Med. 4 97–100
K. T. Dineley X. Xia D. Bui J. D. Sweatt H. Zheng (2002) ArticleTitleAccelerated plaque accumulation, associative learning deficits, and up-regulation of alpha 7 nicotinic receptor protein in transgenic mice co-expressing mutant human presenilin 1 and amyloid precursor proteins J. Biol. Chem. 277 22768–22780 Occurrence Handle10.1074/jbc.M200164200 Occurrence Handle11912199
D. Dam ParticleVan R. D’Hooge M. Staufenbiel C. Ginneken ParticleVan F. Meir ParticleVan P. P. Deyn ParticleDe (2003) ArticleTitleAge-dependent cognitive decline in the APP23 model precedes amyloid deposition Eur. J. Neurosci. 17 388–396 Occurrence Handle10.1046/j.1460-9568.2003.02444.x Occurrence Handle12542676
M. A. Westerman D. Cooper-Blacketer A. Mariash L. Kotilinek T. Kawarabayashi L. H. Younkin G. A. Carlson S. G. Younkin K. H. Ashe (2002) ArticleTitleThe relationship between Abeta and memory in the Tg2576 mouse model of Alzheimer’s disease J. Neurosci. 22 1858–1867 Occurrence Handle11880515
R. Mentlein M. Kolszynski Particlevon R. Sprang R. Lucius (1990) ArticleTitleProline-specific proteases in cultivated neuronal and glial cells Brain Res. 527 159–162 Occurrence Handle10.1016/0006-8993(90)91076-S Occurrence Handle2282478
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Roßner, S., Schulz, I., Zeitschel, U. et al. Brain Prolyl Endopeptidase Expression in Aging, APP Transgenic Mice and Alzheimer’s Disease. Neurochem Res 30, 695–702 (2005). https://doi.org/10.1007/s11064-005-6863-y
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DOI: https://doi.org/10.1007/s11064-005-6863-y