A soluble phosphorylated tau signature links tau, amyloid and the evolution of stages of dominantly inherited Alzheimer's disease.
Adult
Aged
Alzheimer Disease
/ cerebrospinal fluid
Amyloid
/ metabolism
Atrophy
Brain
/ pathology
Cognition
Disease Progression
Female
Fluorodeoxyglucose F18
/ chemistry
Humans
Inheritance Patterns
/ genetics
Magnetic Resonance Imaging
Male
Middle Aged
Neuroimaging
Phosphorylation
Plaque, Amyloid
/ pathology
Solubility
tau Proteins
/ cerebrospinal fluid
Journal
Nature medicine
ISSN: 1546-170X
Titre abrégé: Nat Med
Pays: United States
ID NLM: 9502015
Informations de publication
Date de publication:
03 2020
03 2020
Historique:
received:
11
05
2019
accepted:
30
01
2020
entrez:
13
3
2020
pubmed:
13
3
2020
medline:
9
4
2020
Statut:
ppublish
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.
Identifiants
pubmed: 32161412
doi: 10.1038/s41591-020-0781-z
pii: 10.1038/s41591-020-0781-z
pmc: PMC7309367
mid: NIHMS1584278
doi:
Substances chimiques
Amyloid
0
tau Proteins
0
Fluorodeoxyglucose F18
0Z5B2CJX4D
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
398-407Subventions
Organisme : NIA NIH HHS
ID : P30 AG066444
Pays : United States
Organisme : U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)
ID : R01NS095773
Pays : International
Organisme : NIA NIH HHS
ID : K23 AG046363
Pays : United States
Organisme : NIA NIH HHS
ID : UF1 AG032438
Pays : United States
Organisme : NIA NIH HHS
ID : U19 AG032438
Pays : United States
Organisme : U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)
ID : UF1AG032438
Pays : International
Organisme : RCUK | Medical Research Council (MRC)
ID : MR/L023784/1
Pays : International
Organisme : RCUK | Medical Research Council (MRC)
ID : MR/009076/1
Pays : International
Organisme : NIA NIH HHS
ID : P50 AG005681
Pays : United States
Organisme : U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)
ID : MR/L023784/1
Pays : International
Organisme : NIA NIH HHS
ID : R01 AG052550
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS095773
Pays : United States
Investigateurs
Ricardo Allegri
(R)
Randy Bateman
(R)
Jacob Bechara
(J)
Tammie Benzinger
(T)
Sarah Berman
(S)
Courtney Bodge
(C)
Susan Brandon
(S)
William Bill Brooks
(WB)
Jill Buck
(J)
Virginia Buckles
(V)
Sochenda Chea
(S)
Jasmeer Chhatwal
(J)
Patricio Chrem Mendez
(P)
Helena Chui
(H)
Jake Cinco
(J)
Jack Clifford
(J)
Carlos Cruchaga
(C)
Tamara Donahue
(T)
Jane Douglas
(J)
Noelia Edigo
(N)
Nilufer Erekin-Taner
(N)
Anne Fagan
(A)
Martin Farlow
(M)
Colleen Fitzpatrick
(C)
Gigi Flynn
(G)
Nick Fox
(N)
Erin Franklin
(E)
Hisako Fujii
(H)
Cortaiga Gant
(C)
Samantha Gardener
(S)
Bernardino Ghetti
(B)
Alison Goate
(A)
Jill Goldman
(J)
Brian Gordon
(B)
Neill Graff-Radford
(N)
Julia Gray
(J)
Alexander Groves
(A)
Jason Hassenstab
(J)
Laura Hoechst-Swisher
(L)
David Holtzman
(D)
Russ Hornbeck
(R)
Siri Houeland DiBari
(SH)
Takeshi Ikeuchi
(T)
Snezana Ikonomovic
(S)
Gina Jerome
(G)
Mathias Jucker
(M)
Celeste Karch
(C)
Kensaku Kasuga
(K)
Takeshi Kawarabayashi
(T)
William Bill Klunk
(WB)
Robert Koeppe
(R)
Elke Kuder-Buletta
(E)
Christoph Laske
(C)
Jae-Hong Lee
(JH)
Johannes Levin
(J)
Ralph Martins
(R)
Neal Scott Mason
(NS)
Colin Masters
(C)
Denise Maue-Dreyfus
(D)
Eric McDade
(E)
Hiroshi Mori
(H)
John Morris
(J)
Akem Nagamatsu
(A)
Katie Neimeyer
(K)
James Noble
(J)
Joanne Norton
(J)
Richard Perrin
(R)
Marc Raichle
(M)
Alan Renton
(A)
John Ringman
(J)
Jee Hoon Roh
(JH)
Stephen Salloway
(S)
Peter Schofield
(P)
Hiroyuki Shimada
(H)
Wendy Sigurdson
(W)
Hamid Sohrabi
(H)
Paige Sparks
(P)
Kazushi Suzuki
(K)
Kevin Taddei
(K)
Peter Wang
(P)
Chengjie Xiong
(C)
Xiong Xu
(X)
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