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

被引：439

作者：

Barthelemy, Nicolas R. ^{[1
]}

Li, Yan ^{[1
,2
]}

Joseph-Mathurin, Nelly ^{[3
]}

Gordon, Brian A. ^{[3
]}

Hassenstab, Jason ^{[1
,32
]}

Benzinger, Tammie. L. S. ^{[3
]}

Buckles, Virginia ^{[1
,32
]}

Fagan, Anne M. ^{[1
]}

Perrin, Richard J. ^{[4
]}

Goate, Alison M. ^{[5
]}

Morris, John C. ^{[1
]}

Karch, Celeste M. ^{[6
]}

Xiong, Chengjie ^{[2
,32
]}

Allegri, Ricardo ^{[7
,9
,10
,11
,19
,22
,23
,25
,28
,32
,33
,34
,35
]}

Mendez, Patricio Chrem ^{[7
]}

Berman, Sarah B. ^{[8
]}

Ikeuchi, Takeshi ^{[9
]}

Mori, Hiroshi ^{[10
]}

Shimada, Hiroyuki ^{[10
]}

Shoji, Mikio ^{[11
]}

Suzuki, Kazushi ^{[11
,12
]}

Noble, James ^{[13
,42
]}

Farlow, Martin ^{[14
,35
]}

Chhatwal, Jasmeer ^{[15
,37
,38
]}

Graff-Radford, Neill R. ^{[16
]}

Salloway, Stephen ^{[17
,18
,34
]}

Schofield, Peter R. ^{[19
,20
]}

Masters, Colin L. ^{[21
,22
]}

Martins, Ralph N. ^{[23
]}

O'Connor, Antoinette ^{[24
]}

Fox, Nick C. ^{[24
]}

Levin, Johannes ^{[25
,26
,27
]}

Jucker, Mathias ^{[28
,29
]}

Gabelle, Audrey ^{[30
,31
]}

Lehmann, Sylvain ^{[30
,31
]}

Sato, Chihiro ^{[1
]}

Bateman, Randall J. ^{[1
]}

McDade, Eric ^{[1
,32
]}

Allegri, Ricardo ^{[7
,9
,10
,11
,19
,22
,23
,25
,28
,32
,33
,34
,35
]}

Bateman, Randy ^{[32
]}

Bechara, Jacob ^{[19
]}

Benzinger, Tammie ^{[32
]}

Berman, Sarah ^{[33
]}

Bodge, Courtney ^{[34
]}

Brandon, Susan ^{[32
]}

Brooks, William ^{[19
]}

Buck, Jill ^{[35
]}

Buckles, Virginia ^{[1
,32
]}

Chea, Sochenda ^{[36
]}

机构：

[1] Washington Univ, Sch Med, Dept Neurol, St Louis, MO 63110 USA

[2] Washington Univ, Sch Med, Div Biostat, St Louis, MO 63110 USA

[3] Washington Univ, Sch Med, Dept Radiol, St Louis, MO 63110 USA

[4] Washington Univ, Sch Med, Dept Pathol, St Louis, MO 63110 USA

[5] Icahn Sch Med Mt Sinai, Dept Neurosci, New York, NY 10029 USA

[6] Washington Univ, Sch Med, Dept Psychiat, St Louis, MO 63110 USA

[7] Inst Invest Neurol Raul Correa, Fdn Lucha Enfermedades Neurol Infancia, Buenos Aires, Argentina

[8] Univ Pittsburgh, Sch Med, Pittsburgh, PA USA

[9] Niigata Univ, Niigata, Japan

[10] Osaka City Univ, Osaka, Japan

[11] Hirosaki Univ, Hirosaki, Aomori, Japan

[12] Univ Tokyo, Tokyo, Japan

[13] Columbia Univ, Coll Phys & Surg, New York, NY USA

[14] Indiana Univ, Dept Neurol, Indianapolis, IN 46204 USA

[15] Harvard Med Sch, Massachusetts Gen Hosp, Boston, MA 02115 USA

[16] Mayo Clin Jacksonville, Dept Neurol, Jacksonville, FL USA

[17] Butler Hosp, Providence, RI 02906 USA

[18] Brown Univ, Providence, RI 02912 USA

[19] Neurosci Res Australia, Sydney, NSW, Australia

[20] Univ New South Wales, Sch Med Sci, Sydney, NSW, Australia

[21] Florey Inst Neurosci & Mental Hlth, Melbourne, Vic, Australia

[22] Univ Melbourne, Melbourne, Vic, Australia

[23] Edith Cowan Univ, Perth, WA, Australia

[24] UCL, Inst Neurol, Dementia Res Ctr, London, England

[25] German Ctr Neurodegenerat Dis DZNE, Munich, Germany

[26] Ludwig Maximilians Univ Munchen, Dept Neurol, Munich, Germany

[27] Munich Cluster Syst Neurol SyNergy, Munich, Germany

[28] German Ctr Neurodegenerat Dis DZNE, Tubingen, Germany

[29] Univ Tubingen, Hertie Inst Clin Brain Res, Tubingen, Germany

[30] CHU Montpellier, Lab Biochim & Prote Clin, INSERM UM, Montpellier, France

[31] CHU Montpellier, CRB, INSERM UM, Montpellier, France

[32] Washington Univ, St Louis Sch Med, St Louis, MO USA

[33] Univ Pittsburgh, Pittsburgh, PA USA

[34] Brown Univ, Butler Hosp, Providence, RI 02912 USA

[35] Indiana Univ, Bloomington, IN USA

[36] Mayo Clin Jacksonville, Jacksonville, FL USA

[37] Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA

[38] Massachusetts Gen Hosp, Boston, MA 02114 USA

[39] Univ Southern Calif, Los Angeles, CA 90007 USA

[40] UCL, London, England

[41] Icahn Sch Med Mt Sinai, New York, NY 10029 USA

[42] Columbia Univ, New York, NY USA

[43] Univ Michigan, Ann Arbor, MI 48109 USA

[44] Asan Med Ctr, Seoul, South Korea

[45] Univ Pittsburgh, Med Ctr, Pittsburgh, PA USA

来源：

NATURE MEDICINE | 2020年 / 26卷 / 03期

关键词：

CEREBROSPINAL-FLUID; NEUROFIBRILLARY TANGLES; BETA TOXICITY; PROTEIN-TAU; BIOMARKERS; PLAQUES; PROGRESSION; AGE; ASSOCIATIONS; PREVENTION;

D O I：

10.1038/s41591-020-0781-z

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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. 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-beta 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-beta and neurodegeneration, and may facilitate clinical trials of tau-based treatments.

引用

页码：398 / +

页数：20

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