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 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.
Neuronal Death and Neuroprotection Laboratory, Department of Neuroscience, Mario Negri Institute for Pharmacological Research, Milano 20156, Italy.
Alessandra
A
Sclip
Neuronal Death and Neuroprotection Laboratory, Department of Neuroscience, Mario Negri Institute for Pharmacological Research, Milano 20156, Italy.
Xanthi
X
Antoniou
Neuronal Death and Neuroprotection Laboratory, Department of Neuroscience, Mario Negri Institute for Pharmacological Research, Milano 20156, Italy.
Alessio
A
Colombo
Cardiovascular Research Laboratory, Institute of Physiology, University of Zurich, Zurich 8057, Switzerland.
Giovanni G
GG
Camici
Neuronal Death and Neuroprotection Laboratory, Department of Neuroscience, Mario Negri Institute for Pharmacological Research, Milano 20156, Italy.
Laura
L
Pozzi
Neuronal Death and Neuroprotection Laboratory, Department of Neuroscience, Mario Negri Institute for Pharmacological Research, Milano 20156, Italy.
Daniele
D
Cardinetti
Neuronal Death and Neuroprotection Laboratory, Department of Neuroscience, Mario Negri Institute for Pharmacological Research, Milano 20156, Italy.
Marco
M
Feligioni
Neuronal Death and Neuroprotection Laboratory, Department of Neuroscience, Mario Negri Institute for Pharmacological Research, Milano 20156, Italy.
Pietro
P
Veglianese
Department of Internal Medicine IV, Saarland University Medical Centre, 66421 Homburg/Saar, Germany.
Ferdinand H
FH
Bahlmann
Neuronal Death and Neuroprotection Laboratory, Department of Neuroscience, Mario Negri Institute for Pharmacological Research, Milano 20156, Italy.
Luigi
L
Cervo
Neuronal Death and Neuroprotection Laboratory, Department of Neuroscience, Mario Negri Institute for Pharmacological Research, Milano 20156, Italy.
Claudia
C
Balducci
Clinica Neurologica Division, Università di Perugia, Ospedale S. Maria della Misericordia, Perugia 06156, Italy.
Cinzia
C
Costa
Clinica Neurologica Division, Università di Perugia, Ospedale S. Maria della Misericordia, Perugia 06156, Italy.
Alessandro
A
Tozzi
Clinica Neurologica Division, Università di Perugia, Ospedale S. Maria della Misericordia, Perugia 06156, Italy; Fondazione Santa Lucia, Istituto di Ricovero e Cura a Carattere Scientifico, Rome 00143, Italy.
Paolo
P
Calabresi
Neuronal Death and Neuroprotection Laboratory, Department of Neuroscience, Mario Negri Institute for Pharmacological Research, Milano 20156, Italy.
Gianluigi
G
Forloni
Neuronal Death and Neuroprotection Laboratory, Department of Neuroscience, Mario Negri Institute for Pharmacological Research, Milano 20156, Italy. Electronic address: tiziana.borsello@marionegri.it.
Tiziana
T
Borsello
D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000737:chemistry*; D000818:Animals; D003072:Cognition Disorders / Q000378:metabolism; D004195:Disease Models, Animal; D004594:Electrophysiology; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D018782:Maze Learning; D008569:Memory Disorders / Q000235:genetics; D051379:Mice; D008954:Models, Biological; D010455:Peptides / Q000737:chemistry; D015398:Signal Transduction; D013997:Time Factors
D016229:Amyloid beta-Peptides; D010455:Peptides; D048031:JNK Mitogen-Activated Protein Kinases