c-Jun N-terminal kinase has a key role in Alzheimer disease synaptic dysfunction in vivo.
Altered synaptic function is considered one of the first features of Alzheimer disease (AD). Currently, no treatment is available to prevent the dysfunction of excitatory synapses in AD. Identification of the key modulators of synaptopathy is of particular significance in the treatment of AD. We here characterized the pathways leading to synaptopathy in TgCRND8 mice and showed that c-Jun N-terminal kinase (JNK) is activated at the spine prior to the onset of cognitive impairment. The specific inhibition of JNK, with its specific inhibiting peptide D-JNKI1, prevented synaptic dysfunction in TgCRND8 mice. D-JNKI1 avoided both the loss of postsynaptic proteins and glutamate receptors from the postsynaptic density and the reduction in size of excitatory synapses, reverting their dysfunction. This set of data reveals that JNK is a key signaling pathway in AD synaptic injury and that its specific inhibition offers an innovative therapeutic strategy to prevent spine degeneration in AD.
IRCCS-Istituto di Ricerche Farmacologiche 'Mario Negri', Via La Masa 19, 20156 Milano, Italy.
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Sclip
1] Clinica Neurologica, Università di Perugia, Ospedale S. Maria della Misericordia, S. Andrea delle Fratte, 06156 Perugia, Italy [2] IRCCS-Fondazione S. Lucia, 00179 Roma, Italy.
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Tozzi
Département de Neurosciences Fondamentales, University of Lausanne, 1005 Lausanne, Switzerland.
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Abaza
IRCCS-Istituto di Ricerche Farmacologiche 'Mario Negri', Via La Masa 19, 20156 Milano, Italy.
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Cardinetti
IRCCS-Istituto di Ricerche Farmacologiche 'Mario Negri', Via La Masa 19, 20156 Milano, Italy.
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Colombo
1] Clinica Neurologica, Università di Perugia, Ospedale S. Maria della Misericordia, S. Andrea delle Fratte, 06156 Perugia, Italy [2] IRCCS-Fondazione S. Lucia, 00179 Roma, Italy.
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Calabresi
IRCCS-Istituto di Ricerche Farmacologiche 'Mario Negri', Via La Masa 19, 20156 Milano, Italy.
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Salmona
Département de Neurosciences Fondamentales, University of Lausanne, 1005 Lausanne, Switzerland.
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Welker
IRCCS-Istituto di Ricerche Farmacologiche 'Mario Negri', Via La Masa 19, 20156 Milano, Italy.
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Borsello
D000544:Alzheimer Disease / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics; D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D010455:Peptides / Q000008:administration & dosage; D015398:Signal Transduction; D013569:Synapses / Q000201:enzymology*
D010455:Peptides; D048031:JNK Mitogen-Activated Protein Kinases; C478085:D-JNKI-1