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 A beta 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 A beta oligomers in brain parenchyma of treated mice. In conclusion, by regulating key pathogenic mechanisms of AD, JNK might hold promise as innovative therapeutic target.

c-Jun N-terminal Kinase regulates soluble Abeta oligomers and cognitive impairment in an AD mouse model / A. Sclip, X. Antoniou, A. Colombo, G. Camici, L. Pozzi, D. Cardinetti, M. Feligioni, P. Veglianese, F. Bahlmann, L. Cervo, C. Balducci, C. Costa, A. Tozzi, P. Calabresi, G. Forloni, T. Borsello. - In: JOURNAL OF BIOLOGICAL CHEMISTRY. - ISSN 1083-351X. - 256:51(2011 Dec), pp. 43871-43880. [10.1074/jbc.M111.297515]

c-Jun N-terminal Kinase regulates soluble Abeta oligomers and cognitive impairment in an AD mouse model

T. Borsello
2011-12

Abstract

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 A beta 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 A beta oligomers in brain parenchyma of treated mice. In conclusion, by regulating key pathogenic mechanisms of AD, JNK might hold promise as innovative therapeutic target.
activated protein-kinase; amyloid precursor protein; Alzheimers-disease; tau-hyperphosphorylation; synaptic plasticity; cerebral-ischemia; cell-death; phosphorylation; JNK; stress
Settore BIO/16 - Anatomia Umana
Settore BIO/14 - Farmacologia
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2434/297270
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