MAPT R406W increases tau T217 phosphorylation in absence of amyloid pathology
Abstract Objective Tau hyperphosphorylation at threonine 217 (pT217) in cerebrospinal fluid (CSF) has recently been linked to early amyloidosis and could serve as a highly sensitive biomarker for Alzheimer’s disease (AD). However, it remains unclear whether other tauopathies induce pT217 modificatio...
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Wiley
2021
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oai:doaj.org-article:11eeb562e9e94caa965224e960d997932021-11-19T13:55:31ZMAPT R406W increases tau T217 phosphorylation in absence of amyloid pathology2328-950310.1002/acn3.51435https://doaj.org/article/11eeb562e9e94caa965224e960d997932021-09-01T00:00:00Zhttps://doi.org/10.1002/acn3.51435https://doaj.org/toc/2328-9503Abstract Objective Tau hyperphosphorylation at threonine 217 (pT217) in cerebrospinal fluid (CSF) has recently been linked to early amyloidosis and could serve as a highly sensitive biomarker for Alzheimer’s disease (AD). However, it remains unclear whether other tauopathies induce pT217 modifications. To determine if pT217 modification is specific to AD, CSF pT217 was measured in AD and other tauopathies. Methods Using immunoprecipitation and mass spectrometry methods, we compared CSF T217 phosphorylation occupancy (pT217/T217) and amyloid‐beta (Aβ) 42/40 ratio in cognitively normal individuals and those with symptomatic AD, progressive supranuclear palsy, corticobasal syndrome, and sporadic and familial frontotemporal dementia. Results Individuals with AD had high CSF pT217/T217 and low Aβ42/40. In contrast, cognitively normal individuals and the majority of those with 4R tauopathies had low CSF pT217/T217 and normal Aβ 42/40. We identified a subgroup of individuals with increased CSF pT217/T217 and normal Aβ 42/40 ratio, most of whom were MAPT R406W mutation carriers. Diagnostic accuracies of CSF Aβ 42/40 and CSF pT217/T217, alone and in combination were compared. We show that CSF pT217/T217 × CSF Aβ 42/40 is a sensitive composite biomarker that can separate MAPT R406W carriers from cognitively normal individuals and those with other tauopathies. Interpretation MAPT R406W is a tau mutation that leads to 3R+4R tauopathy similar to AD, but without amyloid neuropathology. These findings suggest that change in CSF pT217/T217 ratio is not specific to AD and might reflect common downstream tau pathophysiology common to 3R+4R tauopathies.Chihiro SatoNipun MallipeddiNupur GhoshalBrenton A. WrightGregory S. DayAlbert A. DavisAlbert H. KimGregory J. ZipfelRandall J. BatemanAudrey GabelleNicolas R. BarthélemyWileyarticleAlzheimer's DiseaseTauopathiestau phosphorylationmass spectrometrycerebrospinal fluidbiomarkerNeurosciences. Biological psychiatry. NeuropsychiatryRC321-571Neurology. Diseases of the nervous systemRC346-429ENAnnals of Clinical and Translational Neurology, Vol 8, Iss 9, Pp 1817-1830 (2021) |
| institution |
DOAJ |
| collection |
DOAJ |
| language |
EN |
| topic |
Alzheimer's Disease Tauopathies tau phosphorylation mass spectrometry cerebrospinal fluid biomarker Neurosciences. Biological psychiatry. Neuropsychiatry RC321-571 Neurology. Diseases of the nervous system RC346-429 |
| spellingShingle |
Alzheimer's Disease Tauopathies tau phosphorylation mass spectrometry cerebrospinal fluid biomarker Neurosciences. Biological psychiatry. Neuropsychiatry RC321-571 Neurology. Diseases of the nervous system RC346-429 Chihiro Sato Nipun Mallipeddi Nupur Ghoshal Brenton A. Wright Gregory S. Day Albert A. Davis Albert H. Kim Gregory J. Zipfel Randall J. Bateman Audrey Gabelle Nicolas R. Barthélemy MAPT R406W increases tau T217 phosphorylation in absence of amyloid pathology |
| description |
Abstract Objective Tau hyperphosphorylation at threonine 217 (pT217) in cerebrospinal fluid (CSF) has recently been linked to early amyloidosis and could serve as a highly sensitive biomarker for Alzheimer’s disease (AD). However, it remains unclear whether other tauopathies induce pT217 modifications. To determine if pT217 modification is specific to AD, CSF pT217 was measured in AD and other tauopathies. Methods Using immunoprecipitation and mass spectrometry methods, we compared CSF T217 phosphorylation occupancy (pT217/T217) and amyloid‐beta (Aβ) 42/40 ratio in cognitively normal individuals and those with symptomatic AD, progressive supranuclear palsy, corticobasal syndrome, and sporadic and familial frontotemporal dementia. Results Individuals with AD had high CSF pT217/T217 and low Aβ42/40. In contrast, cognitively normal individuals and the majority of those with 4R tauopathies had low CSF pT217/T217 and normal Aβ 42/40. We identified a subgroup of individuals with increased CSF pT217/T217 and normal Aβ 42/40 ratio, most of whom were MAPT R406W mutation carriers. Diagnostic accuracies of CSF Aβ 42/40 and CSF pT217/T217, alone and in combination were compared. We show that CSF pT217/T217 × CSF Aβ 42/40 is a sensitive composite biomarker that can separate MAPT R406W carriers from cognitively normal individuals and those with other tauopathies. Interpretation MAPT R406W is a tau mutation that leads to 3R+4R tauopathy similar to AD, but without amyloid neuropathology. These findings suggest that change in CSF pT217/T217 ratio is not specific to AD and might reflect common downstream tau pathophysiology common to 3R+4R tauopathies. |
| format |
article |
| author |
Chihiro Sato Nipun Mallipeddi Nupur Ghoshal Brenton A. Wright Gregory S. Day Albert A. Davis Albert H. Kim Gregory J. Zipfel Randall J. Bateman Audrey Gabelle Nicolas R. Barthélemy |
| author_facet |
Chihiro Sato Nipun Mallipeddi Nupur Ghoshal Brenton A. Wright Gregory S. Day Albert A. Davis Albert H. Kim Gregory J. Zipfel Randall J. Bateman Audrey Gabelle Nicolas R. Barthélemy |
| author_sort |
Chihiro Sato |
| title |
MAPT R406W increases tau T217 phosphorylation in absence of amyloid pathology |
| title_short |
MAPT R406W increases tau T217 phosphorylation in absence of amyloid pathology |
| title_full |
MAPT R406W increases tau T217 phosphorylation in absence of amyloid pathology |
| title_fullStr |
MAPT R406W increases tau T217 phosphorylation in absence of amyloid pathology |
| title_full_unstemmed |
MAPT R406W increases tau T217 phosphorylation in absence of amyloid pathology |
| title_sort |
mapt r406w increases tau t217 phosphorylation in absence of amyloid pathology |
| publisher |
Wiley |
| publishDate |
2021 |
| url |
https://doaj.org/article/11eeb562e9e94caa965224e960d99793 |
| work_keys_str_mv |
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