c-Jun N-terminal Kinase Regulates Soluble Aβ Oligomers and Cognitive Impairment in AD Mouse Model

Alzheimer disease (AD) is characterized by cognitive impairment that starts with memory loss to end in dementia. Loss of synapses and synaptic dysfunction are closely associated with cognitive impairment in AD patients. Biochemical and pathological evidence suggests that soluble Aβ oligomers correla...

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Published in:The Journal of biological chemistry 2011-12, Vol.286 (51), p.43871-43880
Main Authors: Sclip, Alessandra, Antoniou, Xanthi, Colombo, Alessio, Camici, Giovanni G., Pozzi, Laura, Cardinetti, Daniele, Feligioni, Marco, Veglianese, Pietro, Bahlmann, Ferdinand H., Cervo, Luigi, Balducci, Claudia, Costa, Cinzia, Tozzi, Alessandro, Calabresi, Paolo, Forloni, Gianluigi, Borsello, Tiziana
Format: Article
Language:English
Subjects:
Alzheimer Disease - genetics
Alzheimer Disease - metabolism
Amyloid beta-Peptides - chemistry
Amyloid Precursor Protein
Animals
Cell-penetrating Peptides
Cognition Disorders - metabolism
Disease Models, Animal
Electrophysiology
Gene Expression Regulation, Enzymologic
Humans
JNK Mitogen-Activated Protein Kinases - metabolism
Jun N-terminal Kinase (JNK)
Maze Learning
Memory Disorders - genetics
Mice
Models, Biological
Molecular Bases of Disease
Neurodegeneration
Neuroprotection
Peptides - chemistry
Signal Transduction
Soluble Abeta Oligomers
Time Factors
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Summary:Alzheimer disease (AD) is characterized by cognitive impairment that starts with memory loss to end in dementia. Loss of synapses and synaptic dysfunction are closely associated with cognitive impairment in AD patients. Biochemical and pathological evidence suggests that soluble Aβ oligomers correlate with cognitive impairment. Here, we used the TgCRND8 AD mouse model to investigate the role of JNK in long term memory deficits. TgCRND8 mice were chronically treated with the cell-penetrating c-Jun N-terminal kinase inhibitor peptide (D-JNKI1). D-JNKI1, preventing JNK action, completely rescued memory impairments (behavioral studies) as well as the long term potentiation deficits of TgCRND8 mice. Moreover, D-JNKI1 inhibited APP phosphorylation in Thr-668 and reduced the amyloidogenic cleavage of APP and Aβ oligomers in brain parenchyma of treated mice. In conclusion, by regulating key pathogenic mechanisms of AD, JNK might hold promise as innovative therapeutic target. Background: Neuropathological mechanisms in Alzheimer disease (AD) are partially unknown. Results: Chronic JNK inhibition with a cell-permeable peptide (CPP) rescues memory deficits, LTP impairment, and reduces Aβ oligomers in a mouse model that mimics AD. Conclusion: JNK is crucial in AD neurodegenerative mechanisms. Significance: CPPs offer an important tool to interfere with neurodegeneration. JNK is a promising target against AD.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M111.297515