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Inhibition of c-Jun N-terminal kinase activation reverses Alzheimer disease phenotypes in APPswe/PS1dE9 mice


Year of Publication:
Contact PI Name:
Jianting Miao
Contact PI Affiliation:
Department of Neurology, Tangdu Hospital, Fourth Military Medical University, Xi’an City, Shaanxi Province, China
Qiong Zhou, Man Wang, Ying Du, Wei Zhang, Miao Bai, Zhuo Zhang, Zhuyi Li
Primary Reference (PubMED ID):
Funding Source:
National Natural Science Foundation of China
Study Goal and Principal Findings:

The major goal of this study was to investigate the potential disease-modifying effects of SP600125, a small molecule JNK-specific inhibitor, in middle-aged APPswe/PS1dE9 mice. To more closely mimic the clinical setting the authors used 9-month-old APPswe/PS1dE9 mice exhibiting a subset of behavioral and pathological features of AD. Compared with vehicle-treated APPswe/PS1dE9 mice, chronic treatment of SP600125 for 12 weeks potently inhibited JNK activation, which resulted in a marked improvement of behavioral measures of cognitive deficits and a dramatic reduction in amyloid plaque burden, beta-amyloid production, tau hyperphosphorylation, inflammatory responses, and synaptic loss in these transgenic animals. In particular, data showed that SP600125 treatment strongly promoted non-amyloidogenic amyloid precursor protein (APP) processing and inhibited amyloidogenic APP processing via regulating APP-cleavage secretase expression (ie, ADAM10, BACE1, and PS1) in APPswe/PS1dE9 mice. Collectively, these findings demonstrate that specific inhibition of JNK activation by SP600125 treatment is powerfully effective in improving cognitive deficits and reducing multiple neuropathologies associated with AD, suggesting the potential of the specific inhibition of JNK activation by SP600125 treatment as a disease-modifying therapy for AD.

Therapeutic Agent

Therapeutic Information:
Therapy Type:
Small Molecule
Therapeutic Agent:
Therapeutic Target:
c-Jun N-terminal Kinase (JNK)

Animal Model

Model Information:
Model Type:
Strain/Genetic Background:
Not Reported

Experimental Design

Is the following information reported in the study?:
Power/Sample Size Calculation
Randomized into Groups
Blinded for Treatment
Blinded for Outcome Measures
Pharmacokinetic Measures
Pharmacodynamic Measures
Toxicology Measures
ADME Measures
Route of Delivery
Duration of Treatment
Frequency of Administration
Age of Animal at the Beginning of Treatment
Age of Animal at the End of Treatment
Sex as a Biological Variable
Study Balanced for Sex as a Biological Variable
Number of Premature Deaths
Number of Excluded Animals
Statistical Plan
Genetic Background
Inclusion/Exclusion Criteria Included
Conflict of Interest


Outcome Measured
Outcome Parameters
Morris Water Maze
Passive Avoidance Test
beta Amyloid Load
Activated Microglia
Activated Astrocytes
Brain-beta Amyloid Peptide 40
Brain-beta Amyloid Peptide 42
Brain-beta Amyloid Oligomers
Amyloid Precursor Protein (APP) Metabolites
beta-Site Amyloid Precursor Protein Cleaving Enzyme 1 (BACE1)
Insulin Degrading Enzyme (IDE)
A Disintegrin and Metalloproteinase Domain 10 (ADAM10)
Glycogen Synthase Kinase 3 beta (GSK3 beta)
Cyclin-Dependent Kinase 5 (CDK5)
Proinflammatory Markers
Target Engagement (Inhibition c-Jun N-terminal Kinase)
Synaptic Markers
Body Weight
Systemic Tissue Histotoxicity