Pyroglutamate-Aβ: Role in the natural history of Alzheimer's disease |
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| Authors: | Adam P Gunn Colin L Masters Robert A Cherny |
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| Institution: | 1. The Mental Health Research Institute, Parkville, VIC, Australia;2. Centre for Neuroscience, The University of Melbourne, VIC, Australia;3. Department of Pathology, The University of Melbourne, VIC, Australia;1. Department of Neurology, Brigham and Women''s Hospital, Boston, MA, USA;2. Ann Romney Center for Neurologic Diseases, Brigham and Women''s Hospital, Boston, MA, USA;3. Harvard Medical School, Boston, MA, USA;4. Probiodrug AG, Halle (Saale), Germany;5. Harvard NeuroDiscovery Center NeuroBehavior Laboratory Core, Harvard Institutes of Medicine, Boston, MA, USA;1. Albrecht-von-Haller-Institute, University of Göttingen, Justus-von-Liebig-Weg 11, 37077 Göttingen, Germany;2. Probiodrug AG, Weinbergweg 22, 06120 Halle, Germany;1. Institute of Memory and Alzheimer''s Disease (IM2A) and Brain and Spine Institute (ICM) UMR S 1127 Frontlab, Department of Neurology, AP_HP, Pitié-Salpêtrière University Hospital, Sorbonne Universities, Pierre et Marie Curie University, Paris 06, Paris, France;2. AXA Research Fund & UPMC Chair, Paris, France;3. University of British Columbia, Canada;4. Department of Neurology and Alzheimer Center, VU University Medical Center and Neuroscience Campus, Amsterdam, The Netherlands;5. University of Southern California San Diego, CA, USA;6. UMR1027, INSERM, Université Toulouse III, Toulouse University Hospital, France;7. IHU-A-ICM—Institut des Neurosciences translationnelles de Paris, Paris, France;8. INSERM U1146—CNRS UMR 7371—UPMC UM CR2, Site Pitié-Salpêtrière, Paris, France;9. Lübeck Interdisciplinary Platform for Genome Analytics (LIGA), Institutes of Neurogenetics and Integrative and Experimental Genomics, University of Lübeck, Lübeck, Germany;10. School of Public Health, Faculty of Medicine, Imperial College London, London, UK;11. Clinical Neurochemistry Lab, Department of Neuroscience and Physiology, University of Gothenburg, Mölndal Hospital, Sahlgrenska University Hospital, Mölndal, Sweden;12. Federal Institute for Drugs and Medical Devices, Bonn, Germany;13. Laboratory of Alzheimer''s Neuroimaging and Epidemiology, IRCCS Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy;14. Dementia Research Centre, Department of Neurodegenerative Disease, UCL Institute of Neurology, University College London, London, UK;15. INSERM U 1219, Université de Bordeaux, France;p. University Pierre et Marie Curie, Assistance Publique des Hôpitaux de Paris, Alzheimer-Prion Team Institut du Cerveau et de la Moelle (ICM), Paris, France;q. University Hospitals and University of Geneva, Geneva, Switzerland;r. IRCCS Fatebenefratelli, Brescia, Italy;s. McGill Center for Studies in Aging, Douglas Mental Health Research Institute, Montreal, Canada;t. Fondation pour la Recherche sur Alzheimer, Hôpital Pitié-Salpêtrière, Paris, France;u. Department of Clinical Neurophysiology/MEG Center, VU University Medical Center, Amsterdam;v. Sorbonne Universités, UPMC Univ Paris 06, CNRS, INSERM, Laboratoire d''Imagerie Biomédicale, Paris, France;w. AP-HP, Hôpital Pitié-Salpêtrière, Département de Médecine Nucléaire, Paris, France;x. Department of Neurology, Washington University, Hope Center for Neurological Disorders, St. Louis, MO, USA;y. Department of Neurology, Washington University, Knight Alzheimer''s Disease Research Center, St. Louis, MO, USA;z. Center for Alzheimer Research, Karolinska Institutet, Department of Geriatric Medicine, Karolinska University Hospital, Stockholm, Sweden;11. Institute of Clinical Medicine/ Neurology, University of Eastern Finland, Kuopio, Finland;12. Alzheimer''s Disease and Other Cognitive Disorders Unit, Hospital Clínic, Institut d''Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain;13. Barcelonaβeta Brain Research Center, Pasqual Maragall Foundation, Barcelona, Spain;14. Center for Alzheimer''s & Neurodegenerative Disease Research, University of North Texas Health Science Center, TX, USA;15. Memory & Aging Center, Department of Neurology, University of California San Francisco, San Francisco, CA, USA;16. Department of Molecular Imaging, Austin Health, University of Melbourne, Australia;17. Memory and Aging Program, Butler Hospital, Alpert Medical School of Brown University, USA;18. Department of Neurology, Alpert Medical School of Brown University, USA;19. Department of Psychiatry, Alpert Medical School of Brown University, USA;110. Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA;111. Harvard Medical School, Memory Disorders Unit, Center for Alzheimer Research and Treatment, Brigham and Women''s Hospital, Boston, USA;112. Harvard Medical School, Memory Disorders Unit, Center for Alzheimer Research and Treatment, Massachusetts General Hospital, Boston, USA;113. The Alzheimer''s Association Division of Medical & Scientific Relations, Chicago, USA;114. Cleveland Clinic Lou Ruvo Center for Brain Health, Las Vegas, NV, USA;115. Department of Radiology, Mayo Clinic, Rochester MN, USA;3. From the Florey Institute of Neuroscience and Mental Health,;4. Departments of Pathology and;6. Pharmacology and Therapeutics, and;5. Materials Characterisation and Fabrication Platform, University of Melbourne, Parkville, Melbourne 3010, Australia and;1. Nossal Institute for Global Health, University of Melbourne, Australia;2. Beijing Municipal Key Laboratory of Clinical Epidemiology, School of Public Health, Capital Medical University, Beijing, China;3. Johns Hopkins School of Public Health, Baltimore, MD, USA;4. Centre for Population Health Sciences, The University of Edinburgh Medical School, The University of Edinburgh, Edinburgh, UK;5. Centre for Cognitive Ageing and Cognitive Epidemiology, Department of Psychology, The University of Edinburgh, Edinburgh, UK;6. Alzheimer Scotland Dementia Research Centre, Department of Psychology, The University of Edinburgh, Edinburgh, UK;7. Neuroepidemiology and Ageing Research Unit, School of Public Health, Faculty of Medicine, Imperial College London, London, UK;8. Scottish Dementia Clinical Research Network, NHS Scotland, Edinburgh, UK;9. School of Medical Sciences, Edith Cowan University, Perth, Australia;3. Probiodrug AG, Weinbergweg 22, 06120 Halle (Saale), Germany;4. Institute of Biotechnology, Martin Luther University, 06108 Halle-Wittenberg, Germany;5. Department of Molecular Drug Biochemistry and Therapy, Fraunhofer Institute for Cell Therapy and Immunology, Weinbergweg 22, 06120 Halle, Germany;6. SynAging SAS, 54518 Vandoeuvre-les-Nancy, France |
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| Abstract: | The accumulation of amyloid-beta (Aβ) peptides is believed to be a central contributor to the neurodegeneration typically seen in Alzheimer's disease (AD) brain. Aβ extracted from AD brains invariably possesses extensive truncations, yielding peptides of differing N- and C-terminal composition. Whilst Aβ is often abundant in the brains of cognitively normal elderly people, the brains of AD patients are highly enriched for N-terminally truncated Aβ bearing the pyroglutamate modification. Pyroglutamate-Aβ (pE-Aβ) has a higher propensity for oligomerisation and aggregation than full-length Aβ, potentially seeding the accumulation of neurotoxic Aβ oligomers and amyloid deposits. In addition, pE-Aβ has increased resistance to clearance by peptidases, causing these peptides to persist in biological fluids and tissues. The extensive deposition of pE-Aβ in human AD brain is under-represented in many transgenic mouse models of AD, reflecting major differences in the production and processing of Aβ peptides in these models compared to the human disease state. |
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