Journal
JOURNAL OF ALZHEIMERS DISEASE
Volume 81, Issue 4, Pages 1403-1418Publisher
IOS PRESS
DOI: 10.3233/JAD-210297
Keywords
Alzheimer's disease; cognition; propagation; tau; T217-phosphorylation
Categories
Funding
- Science and Technology Committee of China [2016YFC1305800]
- Natural Science Foundation of China [91949205, 31730035, 81721005]
- Special project of technological innovation of Hubei Province [2018ACA142]
- Guangdong Provincial Key ST Program [018B030336001]
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The study showed that T217-phosphorylation exacerbates wild-type tau hyperphosphorylation with aggravated tau cleavage/fibrillization and cognitive impairments; however, overexpressing T217E on the basis P301L does not exacerbate tau phosphorylation or the P301L-induced cognitive deficits, although it aggravates tau cleavage and propagation.
Background: Recent studies show that an increased T217-phosphorylation of tau in plasma could diagnose AD at an early stage with high accuracy and high specificity, while the potential toxic role of tau T217-phosphorylation is not known. Objective: To study the potential toxic role of tau T217-phosphorylation. Methods: We performed stereotactic brain injection, behavioral testing, immunohistochemistry and immunofluorescence, western blotting, Golgi staining, in vitro recombinant tau polymerization, and other measurements. Results: We first constructed tau T217-wild-type (T217), T217-phospho-mimic (T217E), and T217-non-phospho-mimic (T217A) plasmids or their virus vectors on the basis of wild-type tau. We found that expressing tau-T217E induced a significantly increased tau phosphorylation at multiple AD-associated sites with inhibited proteolysis and increased cleavage/fibrillization of tau, while expressing tau-T217A abolished the above changes of tau both in vitro and in vivo. By mutating T217E on tau-P301L, a dominant mutation identified in patients with frontotemporal dementia, we did not observe significant exacerbation of tau-P301L phosphorylation and cognitive impairment although the increased tau cleavage and propagation were shown. Conclusion: T217-phosphorylation exacerbates wild-type tau hyperphosphorylation with aggravated tau cleavage/fibrillization and cognitive impairments, while overexpressing T217E on the basis P301L does not exacerbate tau phosphorylation or the P301L-induced cognitive deficits, although it aggravates tau cleavage and propagation.
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