MAPT R406W increases tau T217 phosphorylation in absence of amyloid pathology.
MAPT R406W increases tau T217 phosphorylation in absence of amyloid pathology.
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DOI：
10.1002/acn3.51435
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发表时间：
2021-09
影响因子：
5.3
通讯作者：
Barthélemy NR
中科院分区：
文献类型：
--
作者：
Sato C;Mallipeddi N;Ghoshal N;Wright BA;Day GS;Davis AA;Kim AH;Zipfel GJ;Bateman RJ;Gabelle A;Barthélemy NR
脑脊液（CSF）中苏氨酸217 （pT217）的Tau过度磷酸化最近与早期淀粉样变性有关，并且可以作为阿尔茨海默病（AD）的高度敏感的生物标志物。然而，尚不清楚其他tau病变是否会诱导pT217修饰。为了确定pT217修饰是否特异于AD，在AD和其他tau病变中测量了CSF pT217。采用免疫沉淀和质谱法，我们比较了认知正常个体和症状性AD、进行性核上性麻痹、皮质基底综合征、散发性和家族性额颞叶痴呆患者脑脊液T217磷酸化占用率（pT217/T217）和淀粉样蛋白β (Aβ) 42/40比率。AD患者脑脊液pT217/T217高，Aβ42/40低。相比之下，认知正常的个体和大多数4R tau病患者的脑脊液pT217/T217较低，Aβ 42/40正常。我们确定了CSF pT217/T217升高和a β 42/40比值正常的个体亚组，其中大多数是MAPT R406W突变携带者。比较单独和联合检测CSF Aβ 42/40和CSF pT217/T217的诊断准确性。我们发现CSF pT217/T217 × CSF a β 42/40是一种敏感的复合生物标志物，可以将MAPT R406W携带者与认知正常个体和其他tau病患者区分开来。MAPT R406W是一种tau突变，可导致类似AD的3R+4R tau病变，但没有淀粉样神经病变。这些发现表明脑脊液pT217/T217比值的变化并非AD特异性的，可能反映了3R+4R tau病共同的下游tau病理生理。
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. 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. 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. 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.
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影响因子：
9.9
作者：
Hu, William T.;Watts, Kelly;Levey, Allan I.
通讯作者：
Levey, Allan I.
影响因子：
9.9
作者：
Hanes J;Kovac A;Kvartsberg H;Kontsekova E;Fialova L;Katina S;Kovacech B;Stevens E;Hort J;Vyhnalek M;Boonkamp L;Novak M;Zetterberg H;Hansson O;Scheltens P;Blennow K;Teunissen CE;Zilka N
通讯作者：
Zilka N
影响因子：
2.4
作者：
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通讯作者：
Wiltfang, Jens
影响因子：
7.1
作者：
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通讯作者：
Sato, Chihiro
影响因子：
8.6
作者：
Aerts, M. B.;Esselink, R. A. J.;Verbeek, M. M.
通讯作者：
Verbeek, M. M.