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| Status |
Public on Nov 15, 2023 |
| Title |
MAPK-DLK signaling coupled with DNA damage promotes intrinsic neurotoxicity associated with non-mutated tau |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Alzheimer’s disease (AD) is the most prevalent form of neurodegeneration. Despite the well-established link between tau aggregation and clinical progression, the major pathways driven by this protein to intrinsically damage neurons are incompletely understood. To model AD-relevant neurodegeneration driven by tau, we overexpressed non-mutated human tau in primary mouse neurons and observed substantial axonal degeneration and cell death, a process accompanied by activated caspase 3. Mechanistically, we detected deformation of the nuclear envelope and increased DNA damage response in tau-expressing neurons. Gene profiling analysis further revealed significant alterations in the mitogen-activated protein kinase (MAPK) pathway; moreover, inhibitors of dual leucine zipper kinase (DLK) and c-Jun N-terminal kinase (JNK) were effective in alleviating wild-type human tau-induced neurodegeneration. In contrast, mutant P301L human tau was less toxic to neurons, despite causing comparable DNA damage. Axonal DLK activation induced by wild-type tau potentiated the impact of DNA damage response, resulting in overt neurotoxicity. In summary, we have established a cellular tauopathy model highly relevant to AD and identified a functional synergy between the MAPK-DLK axis and DNA damage response in the neuronal degenerative process.
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| Overall design |
Primary cultured mouse cortical and hippocampal neurons were infected with/without AAV1-Control, WT tau or P301L. At day 7 after infection, we performed gene expression profiling analysis.
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| Contributor(s) |
Cao W, Li S |
| Citation(s) |
37955806 |
| NIH grant(s) |
| Grant ID |
Grant title |
Affiliation |
Name |
| R01 AG074283 |
Antiviral response coupled with transposon derepression in Alzheimer's disease and aging |
UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON |
Wei Cao |
| RF1 AG057587 |
Interrogating the Interferon Pathway in Aging and Alzheimer's Disease |
BAYLOR COLLEGE OF MEDICINE |
Wei Cao |
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| Submission date |
Oct 25, 2023 |
| Last update date |
Nov 15, 2023 |
| Contact name |
Wei Cao |
| E-mail(s) |
[email protected]
|
| Organization name |
The University of Texas Health Science Center at Houston
|
| Street address |
6431 Fannin Street
|
| City |
Houston |
| State/province |
Texas |
| ZIP/Postal code |
77030 |
| Country |
USA |
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| Platforms (1) |
| GPL17021 |
Illumina HiSeq 2500 (Mus musculus) |
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| Samples (17)
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| Relations |
| BioProject |
PRJNA1032144 |
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