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

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; Méndez, Patricio Chrem; Berman, Sarah B.; Ikeuchi, Takeshi; Mori, Hiroshi; Shimada, Hiroyuki; Shoji, Mikio; Suzuki, Kazushi; Noble, James M.; Farlow, Martin R.; Chhatwal, Jasmeer P.; Graff‐Radford, Neill R.; Salloway, Stephen; Schofield, Peter R.; Masters, Colin L.; Martins, Ralph N.; O’Connor, Antoinette; Fox, Nick C.; Jucker, Mathias; Gabelle, Audrey; Lehmann, Sylvain; Sato, Chihiro; Bateman, Randall J.; McDade, Eric

doi:10.1038/s41591-020-0781-z

Cited by 422 publications

(510 citation statements)

References 66 publications

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“…However, if plasma amyloid-β assays ( Ovod et al , 2017 ; Nakamura et al , 2018 ) are shown to reliably indicate amyloidosis then our data suggest that a blood test alone could be effective for screening for inclusion in trials seeking to reduce tau accumulation rates among cognitively unimpaired individuals. More recently plasma phosphorylated tau assays have been shown to correlate well with tau PET in vivo ( Mielke et al , 2018 ; Barthelemy et al , 2020 ; Karikari et al , 2020 ; Thijssen et al , 2020 ) and with Alzheimer’s disease pathology at autopsy ( Thijssen et al , 2020 ). These studies suggest, but do not prove, that plasma measures could be prognostic of tau accumulation rates.…”

Section: Discussionmentioning

confidence: 99%

Predicting future rates of tau accumulation on PET

Jack

Wiste

Weigand

et al. 2020

Brain

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Clinical trials with anti-tau drugs will need to target individuals at risk of accumulating tau. Our objective was to identify variables available in a research setting that predict future rates of tau PET accumulation separately among individuals who were either cognitively unimpaired or cognitively impaired. All 337 participants had: a baseline study visit with MRI, amyloid PET, and tau PET exams, at least one follow-up tau PET exam; and met clinical criteria for membership in one of two clinical diagnostic groups: cognitively unimpaired (n = 203); or cognitively impaired (n = 134, a combined group of participants with either mild cognitive impairment or dementia with Alzheimer’s clinical syndrome). Our primary analyses were in these two clinical groups; however, we also evaluated subgroups dividing the unimpaired group by normal/abnormal amyloid PET and the impaired group by clinical phenotype (mild cognitive impairment, amnestic dementia, and non-amnestic dementia). Linear mixed effects models were used to estimate associations between age, sex, education, APOE genotype, amyloid and tau PET standardized uptake value ratio (SUVR), cognitive performance, cortical thickness, and white matter hyperintensity volume at baseline, and the rate of subsequent tau PET accumulation. Log-transformed tau PET SUVR was used as the response and rates were summarized as annual per cent change. A temporal lobe tau PET meta-region of interest was used. In the cognitively unimpaired group, only higher baseline amyloid PET was a significant independent predictor of higher tau accumulation rates (P < 0.001). Higher rates of tau accumulation were associated with faster rates of cognitive decline in the cognitively unimpaired subgroup with abnormal amyloid PET (P = 0.03), but among the subgroup with normal amyloid PET. In the cognitively impaired group, younger age (P = 0.02), higher baseline amyloid PET (P = 0.05), APOE ε4 (P = 0.05), and better cognitive performance (P = 0.05) were significant independent predictors of higher tau accumulation rates. Among impaired individuals, faster cognitive decline was associated with faster rates of tau accumulation (P = 0.01). While we examined many possible predictor variables, our results indicate that screening of unimpaired individuals for potential inclusion in anti-tau trials may be straightforward because the only independent predictor of high tau rates was amyloidosis. In cognitively impaired individuals, imaging and clinical variables consistent with early onset Alzheimer’s disease phenotype were associated with higher rates of tau PET accumulation suggesting this may be a highly advantageous group in which to conduct proof-of-concept clinical trials that target tau-related mechanisms. The nature of the dementia phenotype (amnestic versus non-amnestic) did not affect this conclusion.

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Section: Discussionmentioning

confidence: 99%

Predicting future rates of tau accumulation on PET

Jack

Wiste

Weigand

et al. 2020

Brain

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“…Recent studies on familial AD patients have shown that the site-specific phosphorylation state of tau changes in different periods of disease progression [147]. Some sites are phosphorylated (e.g., formation of pTau217 and pTau181) as early as two decades before the development of aggregated tau-pathology.…”

Section: Tau Isoforms Domain Structure Post-translational Modificatmentioning

confidence: 99%

Oligomerization and Conformational Change Turn Monomeric β-Amyloid and Tau Proteins Toxic: Their Role in Alzheimer’s Pathogenesis

2020

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The structural polymorphism and the physiological and pathophysiological roles of two important proteins, β-amyloid (Aβ) and tau, that play a key role in Alzheimer’s disease (AD) are reviewed. Recent results demonstrate that monomeric Aβ has important physiological functions. Toxic oligomeric Aβ assemblies (AβOs) may play a decisive role in AD pathogenesis. The polymorph fibrillar Aβ (fAβ) form has a very ordered cross-β structure and is assumed to be non-toxic. Tau monomers also have several important physiological actions; however, their oligomerization leads to toxic oligomers (TauOs). Further polymerization results in probably non-toxic fibrillar structures, among others neurofibrillary tangles (NFTs). Their structure was determined by cryo-electron microscopy at atomic level. Both AβOs and TauOs may initiate neurodegenerative processes, and their interactions and crosstalk determine the pathophysiological changes in AD. TauOs (perhaps also AβO) have prionoid character, and they may be responsible for cell-to-cell spreading of the disease. Both extra- and intracellular AβOs and TauOs (and not the previously hypothesized amyloid plaques and NFTs) may represent the novel targets of AD drug research.

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“…The finding that Tau becomes aggregated into amyloid filaments in AD and appears hyperphosphorylated triggered an extended search for kinases and phosphatases responsible for Tau's pathological state [reviews, (Martin et al, 2013, Hoffman et al, 2017], as well as searches for P-sites on Tau (Hanger, 2020), and treatments based on these results (Schneider and Mandelkow, 2008). The aim was to identify P-sites as early indicators of pathology in brain tissue, CSF, or in blood (Barthelemy et al, 2020, and as indicators of vulnerable brain circuits affected during Braak stages (Arnsten et al, 2019). In spite of this progress, the relationship between Tau's phosphorylation and aggregation remains enigmatic in view of its exceptional solubility.…”

Section: Significance Of Tau Phosphorylation In Ad Researchmentioning

confidence: 99%

Combinatorial native MS and LC-MS/MS approach reveals high intrinsic phosphorylation of human Tau but minimal levels of other key modifications

Drepper

Biernat

Kaniyappan

et al. 2020

Preprint

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Abnormal changes in the neuronal microtubule-associated protein Tau, such as hyperphosphorylation and aggregation, are considered hallmarks of cognitive deficits in Alzheimer disease. Hyperphosphorylation is thought to take place before aggregation, and therefore it is often assumed that phosphorylation predisposes Tau towards aggregation. However, the nature and extent of phosphorylation has remained ill-defined. Tau protein contains up to 85 potential phosphorylation sites (80 Ser/Thr, and 5 Tyr P-sites), many of which can be phosphorylated by various kinases because the unfolded structure of Tau makes them accessible. However, limitations in methods (e.g. in mass spectrometry of phosphorylated peptides, or antibodies against phospho-epitopes) have led to conflicting results regarding the overall degree of phosphorylation of Tau in cells. Here we present results from a new approach, that is based on native mass spectrometry analysis of intact Tau expressed in a eukaryotic cell system (Sf9) which reveals Tau in different phosphorylation states. The extent of phosphorylation is remarkably heterogeneous with up to ∼20 phosphates (Pi) per molecule and distributed over 51 sites (including all P-sites published so far and additional 18 P-sites). The medium phosphorylated fraction Pm showed overall occupancies centered at 8 Pi (± 5 Pi) with a bell-shaped distribution, the highly phosphorylated fraction Ph had 14 Pi (± 6 Pi). The distribution of sites was remarkably asymmetric (with 71% of all P-sites located in the C-terminal half of Tau). All phosphorylation sites were on Ser or Thr residues, but none on Tyr. Other known posttranslational modifications of Tau were near or below our detection limit (e.g. acetylation, ubiquitination). None of the Tau fractions self-assemble readily, arguing that Tau aggregation is not promoted by phosphorylation per se but requires additional factors.

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

Cited by 422 publications

References 66 publications

Predicting future rates of tau accumulation on PET

Predicting future rates of tau accumulation on PET

Oligomerization and Conformational Change Turn Monomeric β-Amyloid and Tau Proteins Toxic: Their Role in Alzheimer’s Pathogenesis

Combinatorial native MS and LC-MS/MS approach reveals high intrinsic phosphorylation of human Tau but minimal levels of other key modifications

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