Intraneuronal pyroglutamate-Abeta 3–42 triggers neurodegeneration and lethal neurological deficits in a transgenic mouse model

Wirths, Oliver; Breyhan, Henning; Cynis, Holger; Schilling, Stephan; Demuth, Hans-Ulrich; Bayer, Thomas A.

doi:10.1007/s00401-009-0557-5

Cited by 174Alzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration MechanismsDementia and Cognitive Impairment Research

Intraneuronal pyroglutamate-Abeta 3–42 triggers neurodegeneration and lethal neurological deficits in a transgenic mouse model

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Wirths, Oliver, Breyhan, Henning, Cynis, Holger, Schilling, Stephan, Demuth, Hans-Ulrich, Bayer, Thomas A.·2009·Acta Neuropathologica

DOI 10.1007/s00401-009-0557-5PMC PMC2737116

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Abstract

It is well established that only a fraction of Abeta peptides in the brain of Alzheimer's disease (AD) patients start with N-terminal aspartate (Abeta(1D)) which is generated by proteolytic processing of amyloid precursor protein (APP) by BACE. N-terminally truncated and pyroglutamate modified Abeta starting at position 3 and ending with amino acid 42 [Abeta(3(pE)-42)] have been previously shown to represent a major species in the brain of AD patients. When compared with Abeta(1-42), this peptide has stronger aggregation propensity and increased toxicity in vitro. Although it is unknown which peptidases remove the first two N-terminal amino acids, the cyclization of Abeta at N-terminal glutamate can be catalyzed in vitro. Here, we show that Abeta(3(pE)-42) induces neurodegeneration and concomitant neurological deficits in a novel mouse model (TBA2 transgenic mice). Although TBA2 transgenic mice exhibit a strong neuronal expression of Abeta(3-42) predominantly in hippocampus and cerebellum, few plaques were found in the cortex, cerebellum, brain stem and thalamus. The levels of converted Abeta(3(pE)-42) in TBA2 mice were comparable to the APP/PS1KI mouse model with robust neuron loss and associated behavioral deficits. Eight weeks after birth TBA2 mice developed massive neurological impairments together with abundant loss of Purkinje cells. Although the TBA2 model lacks important AD-typical neuropathological features like tangles and hippocampal degeneration, it clearly demonstrates that intraneuronal Abeta(3(pE)-42) is neurotoxic in vivo.

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In TBA2 mice, expression of Aβ3Q-42 resulted in abundant AβpE formation in the hippocampus and Purkinje cell layer, and at ~2 months of age a severe neurological phenotype with growth retardation, loss of motor coordination, and ataxia became evident together with loss of Purkinje cells.
“At ~2 months of age, a severe neurological phenotype with growth retardation, loss of motor coordination, and ataxia became evident, together with AβpE accumulation and loss of Purkinje cells [63].”
From Neuron Loss in Alzheimer’s Disease: Translation in Transgenic Mouse Models (2020) · cites this paper as [63]
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Intraneuronal amyloid β and reduced brain volume in a novel APP T714I mouse model for Alzheimer's disease
Van Broeck, B., Vanhoutte, G., Pirici, D., Van Dam, D., Wils, H., Cuijt, I., Vennekens, K., Zabielski, M., Michalik, A., Theuns, J., et al. (2008) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2006.10.016 · Cited by 60 · see citing works
Association of a Presenilin 1 S170F Mutation With a Novel Alzheimer Disease Molecular Phenotype
Piccini, A., Zanusso, G., Borghi, R., Noviello, C., Monaco, S., Russo, R., Damonte, G., Armirotti, A., Gelati, M., Giordano, R., et al. (2007) · Archives of Neurology · doi:10.1001/archneur.64.5.738 · Cited by 55 · see citing works
Amino‐truncated amyloid β‐peptide (Aβ5‐40/42) produced from caspase‐cleaved amyloid precursor protein is deposited in Alzheimer’s disease brain
Takeda, K., Araki, W., Akiyama, H., & Tabira, T. (2004) · The FASEB Journal · doi:10.1096/fj.03-1070fje · Cited by 53 · see citing works
Comparison of the aggregation properties, secondary structure and apoptotic effects of wild‐type, Flemish and Dutch N‐terminally truncated amyloid β peptides
Demeester, N., Mertens, C., Caster, H., Goethals, M., Vandekerckhove, J. S., Rosseneu, M., & Labeur, C. (2001) · European Journal of Neuroscience · doi:10.1046/j.0953-816x.2001.01579.x · Cited by 38 · see citing works

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Motor deficits, neuron loss, and reduced anxiety coinciding with axonal degeneration and intraneuronal Aβ aggregation in the 5XFAD mouse model of Alzheimer's disease.
Jawhar, S., Trawicka, A., Jenneckens, C., Bayer, T. A., & Wirths, O. (2012) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2010.05.027 · Cited by 623 · see citing works
“…to correlate with neuron loss (Breyhan et al., 009; Christensen et al., 2008; Christensen et al., 2010), as d M 2 s o a F m ( e m g B a ( 6 c G u 2 t w c h n 2 o t r t u h s f e t n ( 2 c a s w p s a d p 3 p a w well as in TBA2 mice expressing pyroglutamate modified A 3-42 (Wirths et al., 2009).”
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Prion-like behaviour and tau-dependent cytotoxicity of pyroglutamylated amyloid-β
Nussbaum, J. M., Schilling, S., Cynis, H., Silva, A., Swanson, E., Wangsanut, T., Tayler, K., Wiltgen, B., Hatami, A., Rönicke, R., et al. (2012) · Nature · doi:10.1038/nature11060 · Cited by 427 · see citing works
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Probing the biology of Alzheimer’s disease in mice
Ashe, K. H., & Zahs, K. R. (2010) · Neuron · doi:10.1016/j.neuron.2010.04.031 · Cited by 413 · see citing works
Amyloid-β and tau complexity — towards improved biomarkers and targeted therapies
Polanco, J. C., Li, C., Bodea, L., Martínez‐Mármol, R., Meunier, F. A., & Götz, J. (2017) · Nature Reviews Neurology · doi:10.1038/nrneurol.2017.162 · Cited by 374 · see citing works
Truncated and modified amyloid-beta species
Kummer, M. P., & Heneka, M. T. (2014) · Alzheimer s Research & Therapy · doi:10.1186/alzrt258 · Cited by 338 · see citing works
Neuropathology and biochemistry of Aβ and its aggregates in Alzheimer’s disease
Thal, D. R., Walter, J., Saido, T. C., & Fändrich, M. (2015) · Acta Neuropathologica · doi:10.1007/s00401-014-1375-y · Cited by 319 · see citing works
Intracellular accumulation of amyloid-beta – a predictor for synaptic dysfunction and neuron loss in Alzheimer’s disease
Bayer (2010) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2010.00008 · Cited by 252 · see citing works
Molecular and Cellular Basis of Neurodegeneration in Alzheimer’s Disease
Jeong, S. (2017) · Molecules and Cells · doi:10.14348/molcells.2017.0096 · Cited by 230 · see citing works
Pyroglutamate Amyloid-β (Aβ): A Hatchet Man in Alzheimer Disease
Jawhar, S., Wirths, O., & Bayer, T. A. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.r111.288308 · Cited by 220 · see citing works
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Actin dynamics and cofilin‐actin rods in alzheimer disease
Bamburg, J. R., & Bernstein, B. W. (2016) · Cytoskeleton · doi:10.1002/cm.21282 · Cited by 181 · see citing works
Transgenic mouse models of alzheimer disease: Developing a better model as a tool for therapeutic interventions.
Kitazawa, M., Medeiros, R., & M. LaFerla, F. (2012) · Current Pharmaceutical Design · doi:10.2174/138161212799315786 · Cited by 178 · see citing works
N-truncated amyloid β (Aβ) 4-42 forms stable aggregates and induces acute and long-lasting behavioral deficits
Bouter, Y., Dietrich, K., Wittnam, J. L., Rezaei-Ghaleh, N., Pillot, T., Papot-Couturier, S., Lefebvre, T., Sprenger, F., Wirths, O., Zweckstetter, M., et al. (2013) · Acta Neuropathologica · doi:10.1007/s00401-013-1129-2 · Cited by 175 · see citing works
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Focusing the amyloid cascade hypothesis on N-truncated Abeta peptides as drug targets against Alzheimer’s disease
Bayer, T. A., & Wirths, O. (2014) · Acta Neuropathologica · doi:10.1007/s00401-014-1287-x · Cited by 168 · see citing works
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Interactions of Pathological Hallmark Proteins
Oláh, J., Vincze, O., Virok, D. P., Simon, D., Bozsó, Z., Tőkési, N., Horváth, I., Hlavanda, E., Kovács, J., Magyar, A., et al. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.243907 · Cited by 156 · see citing works
Passive immunotherapies targeting Aβ and tau in Alzheimer's disease
Plotkin, S. S., & Cashman, N. R. (2020) · Neurobiology of Disease · doi:10.1016/j.nbd.2020.105010 · Cited by 156 · see citing works
Coordination of redox active metal ions to the amyloid precursor protein and to amyloid-β peptides involved in Alzheimer disease. Part 2: Dependence of Cu(II) binding sites with Aβ sequences
Hureau, C., & Dorlet, P. (2012) · Coordination Chemistry Reviews · doi:10.1016/j.ccr.2012.03.034 · Cited by 148 · see citing works
Amyloid‐beta ( A β1–42)‐induced paralysis in C aenorhabditis elegans is inhibited by the polyphenol quercetin through activation of protein degradation pathways
Regitz, C., Dußling, L. M., & Wenzel, U. (2014) · Molecular Nutrition & Food Research · doi:10.1002/mnfr.201400014 · Cited by 142 · see citing works
Proteinopathies, a core concept for understanding and ultimately treating degenerative disorders?
Bayer, T. A. (2013) · European Neuropsychopharmacology · doi:10.1016/j.euroneuro.2013.03.007 · Cited by 141 · see citing works
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Deprotonation of the Asp1Ala2 Peptide Bond Induces Modification of the Dynamic Copper(II) Environment in the Amyloid‐β Peptide near Physiological pH
Hureau, C., Coppel, Y., Dorlet, P., Solari, P. L., Sayen, S., Guillon, E., Sabater, L., & Faller, P. (2009) · Angewandte Chemie International Edition · doi:10.1002/anie.200904512 · Cited by 137 · see citing works
Pyroglutamate-3 Amyloid-β Deposition in the Brains of Humans, Non-Human Primates, Canines, and Alzheimer Disease–Like Transgenic Mouse Models
Frost, J. L., Le, K. X., Cynis, H., Ekpo, E., Kleinschmidt, M., Palmour, R. M., Ervin, F. R., Snigdha, S., Cotman, C. W., Saido, T. C., et al. (2013) · American Journal Of Pathology · doi:10.1016/j.ajpath.2013.05.005 · Cited by 132 · see citing works
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Accumulation of intraneuronal Aβ correlates with ApoE4 genotype
Christensen, D. Z., Schneider-Axmann, T., Lucassen, P. J., Bayer, T. A., & Wirths, O. (2010) · Acta Neuropathologica · doi:10.1007/s00401-010-0666-1 · Cited by 120 · see citing works
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Are N- and C-terminally truncated Aβ species key pathological triggers in Alzheimer's disease?
Dunys, J., Valverde, A., & Checler, F. (2018) · Journal of Biological Chemistry · doi:10.1074/jbc.r118.003999 · Cited by 114 · see citing works
Glutaminyl Cyclase in Human Cortex: Correlation with (pGlu)-Amyloid-β Load and Cognitive Decline in Alzheimer's Disease
Morawski, M., Schilling, S., Kreuzberger, M., Waniek, A., Jäger, C., Koch, B. M., Cynis, H., Kehlen, A., Arendt, T., Hartlage‐Rübsamen, M., et al. (2014) · Journal of Alzheimer s Disease · doi:10.3233/jad-131535 · Cited by 114 · see citing works
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Insights into Alzheimer disease pathogenesis from studies in transgenic animal models
Schaeffer, E. L., Figueiró, M., & Gattaz, W. F. (2011) · Clinics · doi:10.1590/s1807-59322011001300006 · Cited by 114 · see citing works
Overlapping profiles of Aβ peptides in the Alzheimer's disease and pathological aging brains
Moore, B. D., Chakrabarty, P., Levites, Y., Kukar, T. L., Baine, A.-M. T., Moroni, T., Ladd, T. B., Das, P., Dickson, D. W., & Golde, T. E. (2012) · Alzheimer s Research & Therapy · doi:10.1186/alzrt121 · Cited by 112 · see citing works
Oleuropein aglycone protects against pyroglutamylated-3 amyloid-ß toxicity: biochemical, epigenetic and functional correlates
Luccarini, I., Grossi, C., Rigacci, S., Coppi, E., Pugliese, A. M., Pantano, D., la Marca, G., Dami, T. E., Berti, A., Stefani, M., et al. (2014) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2014.08.029 · Cited by 112 · see citing works
Neuron Loss in Transgenic Mouse Models of Alzheimer's Disease
Wirths, O., & Bayer, T. A. (2010) · International Journal of Alzheimer s Disease · doi:10.4061/2010/723782 · Cited by 110 · see citing works
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APP transgenic modeling of Alzheimer’s disease: mechanisms of neurodegeneration and aberrant neurogenesis
Crews, L. A., Rockenstein, E. M., & Masliah, E. (2009) · Brain Structure and Function · doi:10.1007/s00429-009-0232-6 · Cited by 107 · see citing works
Pyroglutamate Abeta pathology in APP/PS1KI mice, sporadic and familial Alzheimer’s disease cases
Wirths, O., Bethge, T., Marcello, A., Harmeier, A., Jawhar, S., Lucassen, P. J., Multhaup, G., Brody, D. L., Esparza, T., Ingelsson, M., et al. (2010) · Journal of Neural Transmission · doi:10.1007/s00702-009-0314-x · Cited by 106 · see citing works
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Zinc(II) Binding Site to the Amyloid-β Peptide: Insights from Spectroscopic Studies with a Wide Series of Modified Peptides
Aliès, B., Conte‐Daban, A., Sayen, S., Collin, F., Kieffer, I., Guillon, E., Faller, P., & Hureau, C. (2016) · Inorganic Chemistry · doi:10.1021/acs.inorgchem.6b01733 · Cited by 106 · see citing works
Overexpression of Glutaminyl Cyclase, the Enzyme Responsible for Pyroglutamate Aβ Formation, Induces Behavioral Deficits, and Glutaminyl Cyclase Knock-out Rescues the Behavioral Phenotype in 5XFAD Mice
Jawhar, S., Wirths, O., Schilling, S., Graubner, S., Demuth, H., & Bayer, T. A. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.185819 · Cited by 105 · see citing works
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Identification of Low Molecular Weight Pyroglutamate Aβ Oligomers in Alzheimer Disease
Wirths, O., Erck, C., Martens, H., Harmeier, A., Geumann, C., Jawhar, S., Kumar, S., Multhaup, G., Walter, J., Ingelsson, M., et al. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.178707 · Cited by 103 · see citing works
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Selective Hippocampal Neurodegeneration in Transgenic Mice Expressing Small Amounts of Truncated Aβ Is Induced by Pyroglutamate–Aβ Formation
Alexandru, A., Jagla, W., Graubner, S., Becker, A., Bäuscher, C., Kohlmann, S., Sedlmeier, R., Raber, K. A., Cynis, H., Rönicke, R., et al. (2011) · The Journal of Neuroscience · doi:10.1523/jneurosci.1794-11.2011 · Cited by 102 · see citing works
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Pyroglutamate Aβ cascade as drug target in Alzheimer’s disease
Bayer, T. A. (2021) · Molecular Psychiatry · doi:10.1038/s41380-021-01409-2 · Cited by 98 · see citing works
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Animal models of amyloid‐β‐related pathologies in Alzheimer’s disease
Philipson, O., Lord, A., Gumucio, A., O'Callaghan, P. W., Lannfelt, L., & Nilsson, L. N. G. (2010) · FEBS Journal · doi:10.1111/j.1742-4658.2010.07564.x · Cited by 98 · see citing works
p53 in neurodegenerative diseases and brain cancers
Checler, F., & da Costa, C. A. (2013) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2013.11.009 · Cited by 97 · see citing works
Intraneuronal Aβ accumulation and neurodegeneration: Lessons from transgenic models
Wirths, O., & Bayer, T. A. (2012) · Life Sciences · doi:10.1016/j.lfs.2012.02.001 · Cited by 91 · see citing works
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Amyloid-β Peptide Aβ3pE-42 Induces Lipid Peroxidation, Membrane Permeabilization, and Calcium Influx in Neurons
Gunn, A. P., Wong, B. X. W., Johanssen, T., Griffith, J. C., Masters, C. L., Bush, A. I., Barnham, K. J., Duce, J. A., & Cherny, R. A. (2016) · Journal of Biological Chemistry · doi:10.1074/jbc.m115.655183 · Cited by 84 · see citing works
Passive Immunization against Pyroglutamate-3 Amyloid-β Reduces Plaque Burden in Alzheimer-Like Transgenic Mice: A Pilot Study
Frost, J. L., Liu, B., Kleinschmidt, M., Schilling, S., Demuth, H., & Lemere, C. A. (2012) · Neurodegenerative Diseases · doi:10.1159/000335913 · Cited by 82 · see citing works
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Brain Pyroglutamate Amyloid-Beta is Produced by Cathepsin B and is Reduced by the Cysteine Protease Inhibitor E64d, Representing a Potential Alzheimer’s Disease Therapeutic
Hook, G. R., Yu, J., Toneff, T., Kindy, M., & Hook, V. (2014) · Journal of Alzheimer's Disease · doi:10.3233/jad-131370 · Cited by 72 · see citing works
Pyroglutamate-Aβ: Role in the natural history of Alzheimer's disease
Gunn, A. P., Masters, C. L., & Cherny, R. A. (2010) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/j.biocel.2010.08.015 · Cited by 79 · see citing works
Pyroglutamate Amyloid β (Aβ) Aggravates Behavioral Deficits in Transgenic Amyloid Mouse Model for Alzheimer Disease
Wittnam, J. L., Portelius, E., Zetterberg, H., Gustavsson, M. K., Schilling, S., Koch, B. C. P., Demuth, H., Blennow, K., Wirths, O., & Bayer, T. A. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.308601 · Cited by 77 · see citing works
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Aβ truncated species: Implications for brain clearance mechanisms and amyloid plaque deposition
Cabrera, E., Mathews, P. M., Mezhericher, E., Beach, T. G., Deng, J., Neubert, T. A., Rostagno, A. A., & Ghiso, J. A. (2017) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2017.07.005 · Cited by 77 · see citing works
Neuron Loss in Alzheimer’s Disease: Translation in Transgenic Mouse Models
Wirths, O., & Zampar, S. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21218144 · Cited by 75 · see citing works
“TBA2 mTRH-Aβ3Q–42 Thy1 No Yes Yes: PN Yes [63]”
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Abeta targets of the biosimilar antibodies of Bapineuzumab, Crenezumab, Solanezumab in comparison to an antibody against N-truncated Abeta in sporadic Alzheimer disease cases and mouse models
Bouter, Y., López‐Noguerola, J. S., Tucholla, P., Crespi, G. A. N., Parker, M. W., Wiltfang, J., Miles, L. A., & Bayer, T. A. (2015) · Acta Neuropathologica · doi:10.1007/s00401-015-1489-x · Cited by 74 · see citing works
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Analysis of microdissected human neurons by a sensitive ELISA reveals a correlation between elevated intracellular concentrations of Aβ42 and Alzheimer’s disease neuropathology
Hashimoto, M., Bogdanovic, N., Volkmann, I., Aoki, M., Winblad, B., & Tjernberg, L. O. (2010) · Acta Neuropathologica · doi:10.1007/s00401-010-0661-6 · Cited by 69 · see citing works
Glutaminyl cyclase contributes to the formation of focal and diffuse pyroglutamate (pGlu)-Aβ deposits in hippocampus via distinct cellular mechanisms
Hartlage‐Rübsamen, M., Morawski, M., Waniek, A., Jäger, C., Zeitschel, U., Koch, B. C. P., Cynis, H., Schilling, S., Schliebs, R., Demuth, H., et al. (2011) · Acta Neuropathologica · doi:10.1007/s00401-011-0806-2 · Cited by 66 · see citing works
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Pyroglutamylated amyloid-β is associated with hyperphosphorylated tau and severity of Alzheimer’s disease
Mandler, M., Walker, L., Santic, R., Hanson, P. S., Upadhaya, A. R., Colloby, S. J., Morris, C. M., Thal, D. R., Thomas, A. J., Schneeberger, A., et al. (2014) · Acta Neuropathologica · doi:10.1007/s00401-014-1296-9 · Cited by 65 · see citing works
Pyroglutamate-Modified Amyloid Beta Peptides: Emerging Targets for Alzheimer´s Disease Immunotherapy
Pérez-Garmendia, R., & Gevorkian, G. (2013) · Current Neuropharmacology · doi:10.2174/1570159x11311050004 · Cited by 65 · see citing works
An anti-pyroglutamate-3 Aβ vaccine reduces plaques and improves cognition in APPswe/PS1ΔE9 mice
Frost, J. L., Liu, B., Rahfeld, J., Kleinschmidt, M., O’Nuallain, B., Le, K. X., Lues, I., Caldarone, B. J., Schilling, S., Demuth, H., et al. (2015) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2015.08.021 · Cited by 63 · see citing works
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Isoglutaminyl cyclase contributes to CCL2-driven neuroinflammation in Alzheimer’s disease
Hartlage‐Rübsamen, M., Waniek, A., Meißner, J., Morawski, M., Schilling, S., Jäger, C., Kleinschmidt, M., Cynis, H., Kehlen, A., Arendt, T., et al. (2015) · Acta Neuropathologica · doi:10.1007/s00401-015-1395-2 · Cited by 61 · see citing works
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Intracellular accumulation of aggregated pyroglutamate amyloid beta: convergence of aging and Aβ pathology at the lysosome
Kimpe, L. D., van Haastert, E. S., Kaminari, A., Zwart, R., Rutjes, H., Hoozemans, J. J. M., & Scheper, W. (2012) · AGE · doi:10.1007/s11357-012-9403-0 · Cited by 60 · see citing works
N-truncated Abeta starting with position four: Early intraneuronal accumulation and rescue of toxicity using NT4X-167, a novel monoclonal antibody
Antonios, G., Saiepour, N., Bouter, Y., Richard, B. C., Paetau, A., Verkkoniemi-Ahola, A., Lannfelt, L., Ingelsson, M., Kovacs, G. G., Pillot, T., et al. (2013) · Acta Neuropathologica Communications · doi:10.1186/2051-5960-1-56 · Cited by 53 · see citing works
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Differential toxicity, conformation and morphology of typical initial aggregation states of Aβ1-42 and Aβpy3-42 beta-amyloids
Galante, D., Corsaro, A., Florio, T., Vella, S., Pagano, A., Sbrana, F., Vassalli, M., Perico, A., & D’Arrigo, C. (2012) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/j.biocel.2012.08.010 · Cited by 51 · see citing works
Cu II Binding to Various Forms of Amyloid‐β Peptides: Are They Friends or Foes?
Borghesani, V., Aliès, B., & Hureau, C. (2017) · European Journal of Inorganic Chemistry · doi:10.1002/ejic.201700776 · Cited by 49 · see citing works
Phosphorylation of the Amyloid-Beta Peptide Inhibits Zinc-Dependent Aggregation, Prevents Na,K-ATPase Inhibition, and Reduces Cerebral Plaque Deposition
Barykin, E. P., Petrushanko, I. Y., Kozin, S. A., Telegin, G. B., Чернов, А. С., Lopina, O. D., Radko, S. P., Mitkevich, V. A., & Makarov, A. А. (2018) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2018.00302 · Cited by 49 · see citing works
The Arctic AβPP mutation leads to Alzheimer’s disease pathology with highly variable topographic deposition of differentially truncated Aβ
Kalimo, H., Lalowski, M. M., Bogdanović, N., Philipson, O., Bird, T. D., Nochlin, D., Schellenberg, G. D., Brundin, R., Olofsson, T., Soliymani, R., et al. (2013) · Acta Neuropathologica Communications · doi:10.1186/2051-5960-1-60 · Cited by 48 · see citing works
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Immunotherapy targeting pyroglutamate-3 Aβ: prospects and challenges
Cynis, H., Frost, J. L., Crehan, H., & Lemere, C. A. (2016) · Molecular Neurodegeneration · doi:10.1186/s13024-016-0115-2 · Cited by 48 · see citing works
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Effector function of anti-pyroglutamate-3 Aβ antibodies affects cognitive benefit, glial activation and amyloid clearance in Alzheimer’s-like mice
Crehan, H., Liu, B., Kleinschmidt, M., Rahfeld, J., Le, K. X., Caldarone, B. J., Frost, J. L., Hettmann, T., Hutter‐Paier, B., O’Nuallain, B., et al. (2020) · Alzheimer s Research & Therapy · doi:10.1186/s13195-019-0579-8 · Cited by 48 · see citing works
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Formic acid is essential for immunohistochemical detection of aggregated intraneuronal Aβ peptides in mouse models of Alzheimer's disease
Christensen, D. Z., Bayer, T. A., & Wirths, O. (2009) · Brain Research · doi:10.1016/j.brainres.2009.09.014 · Cited by 47 · see citing works
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Alzheimer’s Disease: Understanding Motor Impairments
Andrade-Guerrero, J., Martínez-Orozco, H., Villegas-Rojas, M. M., Santiago-Balmaseda, A., Delgado-Minjares, K. M., Pérez‐Segura, I., Baéz-Cortés, M. T., Toro-Colín, M. A. D., Guerra‐Crespo, M., Arias-Carrión, Ó., et al. (2024) · Brain Sciences · doi:10.3390/brainsci14111054 · Cited by 47 · see citing works
Alzheimer’s Disease Model System Using Drosophila
Tsuda, L., & Lim, Y. (2018) · Advances in experimental medicine and biology · doi:10.1007/978-981-13-0529-0_3 · Cited by 46 · see citing works
The value and limitations of transgenic mouse models used in drug discovery for Alzheimer's disease: an update
Bales, K. R. (2012) · Expert Opinion on Drug Discovery · doi:10.1517/17460441.2012.666234 · Cited by 45 · see citing works
Copper Coordination to Native N-Terminally Modified versus Full-Length Amyloid-β: Second-Sphere Effects Determine the Species Present at Physiological pH
Aliès, B., Bijani, C., Sayen, S., Guillon, E., Faller, P., & Hureau, C. (2012) · Inorganic Chemistry · doi:10.1021/ic302097d · Cited by 44 · see citing works
Emerging roles of N- and C-terminally truncated Aβ species in Alzheimer’s disease
Wirths, O., & Zampar, S. (2019) · Expert Opinion on Therapeutic Targets · doi:10.1080/14728222.2019.1702972 · Cited by 44 · see citing works
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Activity and Architecture of Pyroglutamate-Modified Amyloid-β (AβpE3-42) Pores
Gillman, A. L., Jang, H., Lee, J., Ramachandran, S., Kagan, B. L., Nussinov, R., & Arce, F. T. (2014) · The Journal of Physical Chemistry B · doi:10.1021/jp5040954 · Cited by 44 · see citing works
C-Terminal Tetrapeptides Inhibit Aβ42-Induced Neurotoxicity Primarily through Specific Interaction at the N-Terminus of Aβ42
Li, H., Du, Z., Lopes, D. H. J., Fradinger, E. A., Wang, C., & Bitan, G. (2011) · Journal of Medicinal Chemistry · doi:10.1021/jm200982p · Cited by 43 · see citing works
Rationale and study design of a randomized, placebo-controlled, double-blind phase 2b trial to evaluate efficacy, safety, and tolerability of an oral glutaminyl cyclase inhibitor varoglutamstat (PQ912) in study participants with MCI and mild AD—VIVIAD
Vijverberg, E. G. B., Axelsen, T., Bihlet, A. R., Henriksen, K., Weber, F., Fuchs, K., Harrison, J., Kühn‐Wache, K., Alexandersen, P., Prins, N. D., et al. (2021) · Alzheimer s Research & Therapy · doi:10.1186/s13195-021-00882-9 · Cited by 43 · see citing works
Presenilin mouse and zebrafish models for dementia: Focus on neurogenesis
van Tijn, P., Kamphuis, W., Marlatt, M. W., Hol, E. M., & Lucassen, P. J. (2010) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2010.10.008 · Cited by 43 · see citing works
Amyloid Plaque in the Human Brain Can Decompose from Aβ(1-40/1-42) by Spontaneous Nonenzymatic Processes
Lyons, B., Friedrich, M. G., Raftery, M. J., & Truscott, R. J. W. (2016) · Analytical Chemistry · doi:10.1021/acs.analchem.5b03891 · Cited by 43 · see citing works
Transgenic Expression of Intraneuronal Aβ 42 But Not Aβ 40 Leads to Cellular Aβ Lesions, Degeneration, and Functional Impairment without Typical Alzheimer's Disease Pathology
Abramowski, D., Rabe, S., Upadhaya, A. R., Reichwald, J., Danner, S., Staab, D., Capetillo-Zarate, E., Yamaguchi, H., Saido, T. C., Wiederhold, K.-H., et al. (2012) · The Journal of Neuroscience · doi:10.1523/jneurosci.4586-11.2012 · Cited by 41 · see citing works
Intraneuronal Aβ as a trigger for neuron loss: can this be translated into human pathology?
Bayer, T. A., & Wirths, O. (2011) · Biochemical Society Transactions · doi:10.1042/bst0390857 · Cited by 41 · see citing works
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Authors: Wirths, O., Breyhan, H., Cynis, H., Schilling, S., Demuth, H.-U., & Bayer, T. A.
Affiliations: University of Göttingen (DE)
Probiodrug (Germany) (DE)
Corresponding author: Bayer, Thomas A.
ORCID: Wirths, Oliver
Cynis, Holger
Schilling, Stephan
Demuth, Hans-Ulrich
Bayer, Thomas A.
Venue: Acta Neuropathologica
Publisher: Springer Science and Business Media LLC
Published: 2009-06-23
Volume: 118
Issue: 4
Pages: 487-496
ISSN: 0001-6322 (ISSN-L)
1432-0533
DOI: 10.1007/s00401-009-0557-5
PMC: PMC2737116
OpenAlex: W2127458156
Cited by: 174
References: 71
Citations by year: 2026: 1 · 2025: 5 · 2024: 7 · 2023: 10 · 2022: 6 · 2021: 8 · 2020: 6 · 2019: 7 · 2018: 9 · 2017: 9 · 2016: 11 · 2015: 13 · 2014: 18 · 2013: 12 · 2012: 19
FWCI: 11.49
Type: journal article
Language: en
Open access: hybrid
doi.org
Licence: cc-by-nc
Locations: Acta Neuropathologica (publishedVersion, cc-by-nc)
Europe PMC (PubMed Central) (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
GoeScholar The Publication Server of the Georg-August-Universität Göttingen (Georg-August-Universität Göttingen) (submittedVersion, cc-by)
Funders: Alzheimer Forschung Initiative
European Commission (MEST-CT-2005-020013)
Topics: Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords: pyroglutamate amyloid-beta, Alzheimer's disease, neurodegeneration, Purkinje cell degeneration, neurotoxicity, neurological deficit, amyloid precursor protein, BACE, amyloid fibril formation, cerebellum
MeSH terms: Analysis of Variance, Animals, Body Weight, Brain, Brain Diseases, Enzyme-Linked Immunosorbent Assay, Immunohistochemistry, Mice, Transgenic, Nerve Degeneration, Neurons, Peptide Fragments, Phenotype, Purkinje Cells, Amyloid beta-Peptides, Cell Death, Mice

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Intraneuronal pyroglutamate-Abeta 3–42 triggers neurodegeneration and lethal neurological deficits in a transgenic mouse model

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