CDK5-mediated hyperphosphorylation of Tau217 impairs neuronal synaptic structure and exacerbates cognitive impairment in Alzheimer’s disease
Abstract Numerous studies have demonstrated that tau phosphorylated at threonine 217 (p-T217) in cerebrospinal fluid (CSF) or plasma is a potential biomarker for Alzheimer’s disease (AD). However, the detailed pathological effects of elevated p-T217 and the mechanisms underlying T217 phosphorylation...
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2025-08-01
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| Series: | Translational Psychiatry |
| Online Access: | https://doi.org/10.1038/s41398-025-03551-9 |
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| author | Kangyue Fu Nan Lin Yiwen Xu En Huang Raoli He Zhixin Wu Dianbo Qu Xiaochun Chen Tianwen Huang |
| author_facet | Kangyue Fu Nan Lin Yiwen Xu En Huang Raoli He Zhixin Wu Dianbo Qu Xiaochun Chen Tianwen Huang |
| author_sort | Kangyue Fu |
| collection | DOAJ |
| description | Abstract Numerous studies have demonstrated that tau phosphorylated at threonine 217 (p-T217) in cerebrospinal fluid (CSF) or plasma is a potential biomarker for Alzheimer’s disease (AD). However, the detailed pathological effects of elevated p-T217 and the mechanisms underlying T217 phosphorylation remain incompletely understood. In this study, we revealed a role of tau phosphorylated at T217 in AD. In 5 × FAD mice, increased p-T217 levels, correlated with CDK5 activation, were associated with neurite damage and neuronal apoptosis. Mice expressing a phospho-mimetic T217E mutant in the hippocampus exhibited significant learning impairments in the Morris water maze and Y-Maze test, along with reduced levels of the synaptic proteins Drebrin and PSD95. Electron microscopy revealed severe synaptic and microtubules damage in these mice, along with disrupted axonal structures confirmed by Golgi staining. Additionally, hyperactivation of CDK5 through p25 overexpression increased T217 phosphorylation, whereas CDK5 inactivation reduced it. The study concludes that CDK5 mediated Tau phosphorylation at T217 contributes to synaptic damage and cognitive deficits, highlighting it as a potential therapeutic target for AD. |
| format | Article |
| id | doaj-art-98623aa4a75343e69d799002ba7fcdff |
| institution | Kabale University |
| issn | 2158-3188 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Translational Psychiatry |
| spelling | doaj-art-98623aa4a75343e69d799002ba7fcdff2025-08-24T11:51:39ZengNature Publishing GroupTranslational Psychiatry2158-31882025-08-0115111110.1038/s41398-025-03551-9CDK5-mediated hyperphosphorylation of Tau217 impairs neuronal synaptic structure and exacerbates cognitive impairment in Alzheimer’s diseaseKangyue Fu0Nan Lin1Yiwen Xu2En Huang3Raoli He4Zhixin Wu5Dianbo Qu6Xiaochun Chen7Tianwen Huang8Department of Neurology, Fujian Medical University Union HospitalFujian Key Laboratory of Vascular Aging, Department of Geriatrics, Fujian Medical University Union HospitalDepartment of Neurology, Fujian Medical University Union HospitalDepartment of Neurology, Fujian Medical University Union HospitalDepartment of Neurology, Fujian Medical University Union HospitalDepartment of Neurology, Fujian Medical University Union HospitalDepartment of Cellular and Molecular Medicine, Faculty of Medicine, University of OttawaDepartment of Neurology, Fujian Medical University Union HospitalDepartment of Neurology, Fujian Medical University Union HospitalAbstract Numerous studies have demonstrated that tau phosphorylated at threonine 217 (p-T217) in cerebrospinal fluid (CSF) or plasma is a potential biomarker for Alzheimer’s disease (AD). However, the detailed pathological effects of elevated p-T217 and the mechanisms underlying T217 phosphorylation remain incompletely understood. In this study, we revealed a role of tau phosphorylated at T217 in AD. In 5 × FAD mice, increased p-T217 levels, correlated with CDK5 activation, were associated with neurite damage and neuronal apoptosis. Mice expressing a phospho-mimetic T217E mutant in the hippocampus exhibited significant learning impairments in the Morris water maze and Y-Maze test, along with reduced levels of the synaptic proteins Drebrin and PSD95. Electron microscopy revealed severe synaptic and microtubules damage in these mice, along with disrupted axonal structures confirmed by Golgi staining. Additionally, hyperactivation of CDK5 through p25 overexpression increased T217 phosphorylation, whereas CDK5 inactivation reduced it. The study concludes that CDK5 mediated Tau phosphorylation at T217 contributes to synaptic damage and cognitive deficits, highlighting it as a potential therapeutic target for AD.https://doi.org/10.1038/s41398-025-03551-9 |
| spellingShingle | Kangyue Fu Nan Lin Yiwen Xu En Huang Raoli He Zhixin Wu Dianbo Qu Xiaochun Chen Tianwen Huang CDK5-mediated hyperphosphorylation of Tau217 impairs neuronal synaptic structure and exacerbates cognitive impairment in Alzheimer’s disease Translational Psychiatry |
| title | CDK5-mediated hyperphosphorylation of Tau217 impairs neuronal synaptic structure and exacerbates cognitive impairment in Alzheimer’s disease |
| title_full | CDK5-mediated hyperphosphorylation of Tau217 impairs neuronal synaptic structure and exacerbates cognitive impairment in Alzheimer’s disease |
| title_fullStr | CDK5-mediated hyperphosphorylation of Tau217 impairs neuronal synaptic structure and exacerbates cognitive impairment in Alzheimer’s disease |
| title_full_unstemmed | CDK5-mediated hyperphosphorylation of Tau217 impairs neuronal synaptic structure and exacerbates cognitive impairment in Alzheimer’s disease |
| title_short | CDK5-mediated hyperphosphorylation of Tau217 impairs neuronal synaptic structure and exacerbates cognitive impairment in Alzheimer’s disease |
| title_sort | cdk5 mediated hyperphosphorylation of tau217 impairs neuronal synaptic structure and exacerbates cognitive impairment in alzheimer s disease |
| url | https://doi.org/10.1038/s41398-025-03551-9 |
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