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Background: Chronic neuroinflammation, aggressive amyloid beta (Aβ) deposition, neuronal cell loss and cognitive impairment are pathological symptoms of Alzheimer’s disease (AD). Regarding these symptoms, resolution of neuroinflammation and inhibition of Aβ-driven pathology might be a novel strategy for AD therapy. Efforts to prevent AD progression have identified that p38 mitogen-activated protein kinase (MAPK) is a promising target for AD therapy. However, the actual therapeutic effect of selective p38 MAPK inhibition in AD has not been ascertained yet.
Methods: In this study, we explored the therapeutic potential of NJK14047, a selective p38 MAPK inhibitor, using an Alzheimer’s disease mouse model, 5XFAD. The mice were injected 2.5 mg/kg NJK14047 or vehicle every other day for 3 months. Morris water maze task and histological imaging analysis were performed. Protein and mRNA expression levels were measured using immunoblotting and qRT-PCR. In in vitro studies, the cytotoxicity of microglial conditioned medium and astrocyte conditioned medium on primary neurons were measured using MTT assay and TUNEL assay.
Results: NJK14047 treatment downregulated phospho-p38 MAPK levels, decreased the amount of Aβ deposits, and improved spatial learning memory in 5XFAD mice. Interestingly, these effects were associated with the decrease of inflammatory responses and the elevation of alternatively activated M2 markers. Furthermore, NJK14047 treatment reduced the number of Fluoro-jade B positive cells, a class of degenerating neurons, in the brains of 5XFAD mice. The neuroprotective effect of NJK14047, achieved via the restoration of microglia function, was further confirmed by in vitro studies.
Conclusion: Taken together, our results reveal that inhibition of p38 MAPK in the brain alleviates AD pathology and represents a potential strategy for AD therapy. It also suggests that NJK14047 is a promising candidate for AD treatment. Keywords : Alzheimer’s disease, Amyloid-β, P38 mitogen-activated protein kinase, Kinase inhibitor, Microglia
Keywords
Alzheimer’s disease, Amyloid-β, P38 mitogen-activated protein kinase, Kinase inhibitor, Microglia
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CURRENT STATUS: Published
View the published article at Alzheimer's Research & Therapy.
No community comments so far
Editorial decision: Accept
On 07 Apr, 2020
Reviewer #2 agreed
On 28 Mar, 2020
Review #2 received
Received 28 Mar, 2020
Review #1 received
Received 28 Mar, 2020
Reviewer #1 agreed
On 27 Mar, 2020
Reviewers invited
Invitations sent on 25 Mar, 2020
Editor assigned
On 25 Mar, 2020
Submission checks complete
On 24 Mar, 2020
Editor invited
On 24 Mar, 2020
No comments provided
Editorial decision: Minor Revision
On 29 Feb, 2020
Reviewer #1 agreed
On 26 Feb, 2020
Reviewer #2 agreed
On 26 Feb, 2020
Review #1 received
Received 26 Feb, 2020
Review #2 received
Received 26 Feb, 2020
Reviewers invited
Invitations sent on 25 Feb, 2020
Editor assigned
On 24 Feb, 2020
Submission checks complete
On 23 Feb, 2020
Editor invited
On 23 Feb, 2020
Version 1
Posted 20 Jan, 2020
No comments provided
Editorial decision: Major Revision
On 03 Feb, 2020
Review #2 received
Received 02 Feb, 2020
Reviewer #2 agreed
On 30 Jan, 2020
Review #1 received
Received 29 Jan, 2020
Reviewers invited
Invitations sent on 18 Jan, 2020
Reviewer #1 agreed
On 18 Jan, 2020
Editor assigned
On 15 Jan, 2020
First submitted
On 14 Jan, 2020
Submission checks complete
On 14 Jan, 2020
Editor invited
On 14 Jan, 2020
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Subject Areas
Cognitive Neuroscience
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A new preprint design is coming!
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See the published version of this preprint at Alzheimer's Research & Therapy.
This is a preprint, a preliminary version of a manuscript that has not completed peer review at a journal. Research Square does not conduct peer review prior to posting preprints. The posting of a preprint on this server should not be interpreted as an endorsement of its validity or suitability for dissemination as established information or for guiding clinical practice.
Learn more about In Review
Research
Badges
Prescreen
This manuscript passed our Prescreen assessment
Complete author information
Appropriate declaration statements
Potential risks to human health
Prescreen
Peer Review Timeline
CURRENT STATUS: Published
View the published article at Alzheimer's Research & Therapy.
No community comments so far
Editorial decision: Accept
On 07 Apr, 2020
Reviewer #2 agreed
On 28 Mar, 2020
Review #2 received
Received 28 Mar, 2020
Review #1 received
Received 28 Mar, 2020
Reviewer #1 agreed
On 27 Mar, 2020
Reviewers invited
Invitations sent on 25 Mar, 2020
Editor assigned
On 25 Mar, 2020
Submission checks complete
On 24 Mar, 2020
Editor invited
On 24 Mar, 2020
No comments provided
Editorial decision: Minor Revision
On 29 Feb, 2020
Reviewer #1 agreed
On 26 Feb, 2020
Reviewer #2 agreed
On 26 Feb, 2020
Review #1 received
Received 26 Feb, 2020
Review #2 received
Received 26 Feb, 2020
Reviewers invited
Invitations sent on 25 Feb, 2020
Editor assigned
On 24 Feb, 2020
Submission checks complete
On 23 Feb, 2020
Editor invited
On 23 Feb, 2020
Version 1
Posted 20 Jan, 2020
No comments provided
Editorial decision: Major Revision
On 03 Feb, 2020
Review #2 received
Received 02 Feb, 2020
Reviewer #2 agreed
On 30 Jan, 2020
Review #1 received
Received 29 Jan, 2020
Reviewers invited
Invitations sent on 18 Jan, 2020
Reviewer #1 agreed
On 18 Jan, 2020
Editor assigned
On 15 Jan, 2020
First submitted
On 14 Jan, 2020
Submission checks complete
On 14 Jan, 2020
Editor invited
On 14 Jan, 2020
Metrics
Comments: 0
PDF Downloads: ...
HTML Views: ...
Subject Areas
Cognitive Neuroscience
License:
This work is licensed under a CC BY 4.0 License. Read Full License
View the published article at Alzheimer's Research & Therapy.
Background: Chronic neuroinflammation, aggressive amyloid beta (Aβ) deposition, neuronal cell loss and cognitive impairment are pathological symptoms of Alzheimer’s disease (AD). Regarding these symptoms, resolution of neuroinflammation and inhibition of Aβ-driven pathology might be a novel strategy for AD therapy. Efforts to prevent AD progression have identified that p38 mitogen-activated protein kinase (MAPK) is a promising target for AD therapy. However, the actual therapeutic effect of selective p38 MAPK inhibition in AD has not been ascertained yet.
Methods: In this study, we explored the therapeutic potential of NJK14047, a selective p38 MAPK inhibitor, using an Alzheimer’s disease mouse model, 5XFAD. The mice were injected 2.5 mg/kg NJK14047 or vehicle every other day for 3 months. Morris water maze task and histological imaging analysis were performed. Protein and mRNA expression levels were measured using immunoblotting and qRT-PCR. In in vitro studies, the cytotoxicity of microglial conditioned medium and astrocyte conditioned medium on primary neurons were measured using MTT assay and TUNEL assay.
Results: NJK14047 treatment downregulated phospho-p38 MAPK levels, decreased the amount of Aβ deposits, and improved spatial learning memory in 5XFAD mice. Interestingly, these effects were associated with the decrease of inflammatory responses and the elevation of alternatively activated M2 markers. Furthermore, NJK14047 treatment reduced the number of Fluoro-jade B positive cells, a class of degenerating neurons, in the brains of 5XFAD mice. The neuroprotective effect of NJK14047, achieved via the restoration of microglia function, was further confirmed by in vitro studies.
Conclusion: Taken together, our results reveal that inhibition of p38 MAPK in the brain alleviates AD pathology and represents a potential strategy for AD therapy. It also suggests that NJK14047 is a promising candidate for AD treatment. Keywords : Alzheimer’s disease, Amyloid-β, P38 mitogen-activated protein kinase, Kinase inhibitor, Microglia
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