A soluble phosphorylated tau signature links tau, amyloid and the evolution of stages of dominantly inherited Alzheimer’s disease

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 i...

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Vydané v:	Nature Medicine Ročník 26; číslo 3; s. 398 - 407
Hlavní autori:	Barthélemy, Nicolas R., Li, Yan, Joseph-Mathurin, Nelly, Gordon, Brian A., Hassenstab, Jason, Benzinger, Tammie. L. S., Buckles, Virginia, Fagan, Anne M., Perrin, Richard J., Goate, Alison M., Morris, John C., Karch, Celeste M., Xiong, Chengjie, Allegri, Ricardo, Mendez, Patricio Chrem, Berman, Sarah B., Ikeuchi, Takeshi, Mori, Hiroshi, Shimada, Hiroyuki, Shoji, Mikio, Suzuki, Kazushi, Noble, James, Farlow, Martin, Chhatwal, Jasmeer, Graff-Radford, Neill R., Salloway, Stephen, Schofield, Peter R., Masters, Colin L., Martins, Ralph N., O’Connor, Antoinette, Fox, Nick C., Levin, Johannes, Jucker, Mathias, Gabelle, Audrey, Lehmann, Sylvain, Sato, Chihiro, Bateman, Randall J., McDade, Eric
Médium:	Journal Article Magazine Article
Jazyk:	English
Vydavateľské údaje:	New York Nature Publishing Group US 01.03.2020 Nature Publishing Group
Predmet:	631/378/2612 692/53/2421 692/617 Adult Aged Alzheimer Disease - cerebrospinal fluid Alzheimer Disease - diagnostic imaging Alzheimer Disease - genetics Alzheimer Disease - metabolism Alzheimer's disease Amyloid Amyloid - metabolism Amyloid beta-protein Atrophy Biomedical and Life Sciences Biomedicine Brain - pathology Cancer Research Cerebrospinal fluid Clinical trials Cognition Cognitive ability Development and progression Disease Progression Female Fluorodeoxyglucose F18 - chemistry Health aspects Humans Hypometabolism Infectious Diseases Inheritance Patterns - genetics Kinases Life Sciences Magnetic Resonance Imaging Male Markers Metabolic Diseases Middle Aged Molecular Medicine Neurodegeneration Neurodegenerative diseases Neuroimaging Neurosciences Pathology Phosphorylation Plaque, Amyloid - pathology Solubility Tau protein tau Proteins - cerebrospinal fluid tau Proteins - metabolism China
ISSN:	1078-8956, 1546-170X, 1546-170X, 1744-7933
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Shrnutí:	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. Site-specific hyperphosphorylations of tau in the cerebrospinal fluid change with disease course, and correlate with pathology and cognitive decline in dominantly inherited Alzheimer’s disease.
Bibliografia:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 PMCID: PMC7309367 A list of members and affiliations appears at the end of the paper. N.R.B. and C.S. performed the mass spectrometry analyses. Y.L., C.X., N.J.-M. and B.A.G. performed the statistical and imaging analyses. N.R.B., Y.L., R.J.B. and E.M. designed the study and wrote the initial draft of the manuscript. All authors collected samples and data, helped to interpret the results and reviewed drafts of the manuscript. Author contributions
ISSN:	1078-8956 1546-170X 1546-170X 1744-7933
DOI:	10.1038/s41591-020-0781-z