A soluble phosphorylated tau signature links tau, amyloid and the evolution of stages of dominantly inherited Alzheimer’s disease
Nicolas Barthélemy
(1)
,
Yan Li
(1)
,
Nelly Joseph-Mathurin
(1)
,
Brian Gordon
(1)
,
Jason Hassenstab
(1)
,
Tammie. Benzinger
(1)
,
Virginia Buckles
(1)
,
Anne Fagan
(1)
,
Richard Perrin
(1)
,
Alison Goate
(2)
,
John Morris
(1)
,
Celeste Karch
(1)
,
Chengjie Xiong
(1)
,
Ricardo Allegri
(3)
,
Patricio Chrem Mendez
(3)
,
Sarah Berman
(4)
,
Takeshi Ikeuchi
(5)
,
Hiroshi Mori
(6)
,
Hiroyuki Shimada
(6)
,
Mikio Shoji
(7)
,
Kazushi Suzuki
(8)
,
James Noble
(9)
,
Martin Farlow
(10)
,
Jasmeer Chhatwal
(11)
,
Neill Graff-Radford
(12)
,
Stephen Salloway
(13)
,
Peter Schofield
(14, 15)
,
Colin Masters
(16, 17)
,
Ralph Martins
(18)
,
Antoinette O’connor
(19)
,
Nick Fox
(19)
,
Johannes Levin
(20, 21, 22)
,
Mathias Jucker
(20, 23)
,
Audrey Gabelle
(24, 25)
,
Sylvain Lehmann
(24, 25)
,
Chihiro Sato
(1)
,
Randall Bateman
(1)
,
Eric Mcdade
(1)
1
Washington University School of Medicine in St. Louis
2 MSSM - Icahn School of Medicine at Mount Sinai [New York]
3 FLENI - Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia [Buenos Aires]
4 University of Pittsburgh School of Medicine
5 Niigata University
6 OCU - Osaka City University
7 Hirosaki University
8 UTokyo - The University of Tokyo
9 Columbia University [New York]
10 IUPUI - Indiana University - Purdue University Indianapolis
11 HMS - Harvard Medical School [Boston]
12 Mayo Clinic [Jacksonville]
13 Brown University
14 NeuRA - Neuroscience Research Australia
15 UNSW - University of New South Wales [Sydney]
16 The Florey Institute of Neuroscience and Mental Health
17 University of Melbourne
18 ECU - Edith Cowan University
19 UCL - University College of London [London]
20 DZNE - German Research Center for Neurodegenerative Diseases - Deutsches Zentrum für Neurodegenerative Erkrankungen
21 LMU - Ludwig Maximilian University [Munich] = Ludwig Maximilians Universität München
22 SyNergy - Munich Cluster for systems neurology [Munich]
23 University of Tübingen
24 CHRU Montpellier - Centre Hospitalier Régional Universitaire [Montpellier]
25 BCM - BioCampus
2 MSSM - Icahn School of Medicine at Mount Sinai [New York]
3 FLENI - Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia [Buenos Aires]
4 University of Pittsburgh School of Medicine
5 Niigata University
6 OCU - Osaka City University
7 Hirosaki University
8 UTokyo - The University of Tokyo
9 Columbia University [New York]
10 IUPUI - Indiana University - Purdue University Indianapolis
11 HMS - Harvard Medical School [Boston]
12 Mayo Clinic [Jacksonville]
13 Brown University
14 NeuRA - Neuroscience Research Australia
15 UNSW - University of New South Wales [Sydney]
16 The Florey Institute of Neuroscience and Mental Health
17 University of Melbourne
18 ECU - Edith Cowan University
19 UCL - University College of London [London]
20 DZNE - German Research Center for Neurodegenerative Diseases - Deutsches Zentrum für Neurodegenerative Erkrankungen
21 LMU - Ludwig Maximilian University [Munich] = Ludwig Maximilians Universität München
22 SyNergy - Munich Cluster for systems neurology [Munich]
23 University of Tübingen
24 CHRU Montpellier - Centre Hospitalier Régional Universitaire [Montpellier]
25 BCM - BioCampus
Nicolas Barthélemy
- Fonction : Auteur
- PersonId : 792183
- ORCID : 0000-0003-4937-2860
Yan Li
- Fonction : Auteur
- PersonId : 763439
- ORCID : 0000-0002-6336-0981
Brian Gordon
- Fonction : Auteur
- PersonId : 817987
- ORCID : 0000-0003-2109-2955
Tammie. Benzinger
- Fonction : Auteur
- PersonId : 817988
- ORCID : 0000-0002-8114-0552
Alison Goate
- Fonction : Auteur
- PersonId : 761457
- ORCID : 0000-0002-0576-2472
- IdRef : 186309759
John Morris
- Fonction : Auteur
- PersonId : 782575
- ORCID : 0000-0003-0290-7979
Celeste Karch
- Fonction : Auteur
- PersonId : 800011
- ORCID : 0000-0002-6854-5547
Jasmeer Chhatwal
- Fonction : Auteur
- PersonId : 817990
- ORCID : 0000-0002-7792-1698
Peter Schofield
- Fonction : Auteur
- PersonId : 804021
- ORCID : 0000-0003-2967-9662
Mathias Jucker
- Fonction : Auteur
- PersonId : 808298
- ORCID : 0000-0001-9045-1072
Audrey Gabelle
- Fonction : Auteur
- PersonId : 757644
- ORCID : 0000-0002-7648-9194
Sylvain Lehmann
- Fonction : Auteur
- PersonId : 757920
- ORCID : 0000-0001-6117-562X
- IdRef : 079263305
Chihiro Sato
- Fonction : Auteur
- PersonId : 760241
- ORCID : 0000-0002-7639-8727
Randall Bateman
- Fonction : Auteur
- PersonId : 800012
- ORCID : 0000-0002-7729-1702
Eric Mcdade
- Fonction : Auteur
- PersonId : 817991
- ORCID : 0000-0002-6764-3866
Résumé
Development of tau-based therapies for Alzheimer's disease requires an understanding of the timing of disease-related changes in tau. We quantified the phosphorylation state at multiple sites of the tau protein in cerebrospinal fluid markers across four decades of disease progression in dominantly inherited Alzheimer's disease. We identified a pattern of tau staging where site-specific phosphorylation changes occur at different periods of disease progression and follow distinct trajectories over time. These tau phosphorylation state changes are uniquely associated with structural, metabolic, neurodegenerative and clinical markers of disease, and some (p-tau217 and p-tau181) begin with the initial increases in aggregate amyloid-β as early as two decades before the development of aggregated tau pathology. Others (p-tau205 and t-tau) increase with atrophy and hypometabolism closer to symptom onset. These findings provide insights into the pathways linking tau, amyloid-β and neurodegeneration, and may facilitate clinical trials of tau-based treatments.
Domaines
Sciences du Vivant [q-bio]
Origine : Fichiers produits par l'(les) auteur(s)