Secretion of Amyloid-beta peptide (Aβ) circulating oligomers and their aggregate forms derived by processing of beta-amyloid precursor protein (APP) are a key event in Alzheimer's disease (AD). We show that phosphorylation of APP on threonine 668 may play a role in APP metabolism in H4-APPswcell line, a degenerative AD model. We proved that JNK plays a fundamental role in this phosphorylation since its specific inhibition, with the JNK inhibitor peptide (D-JNKI1), induced APP degradation and prevented APP phosphorylation at T668. This results in a significant drop of βAPPs, Aβ fragments and Aβ circulating oligomers. Moreover the D-JNKI1 treatment produced a switch in the APP metabolism, since the peptide reduced the rate of the amyloidogenic processing in favour of the non-amyloidogenic one. All together our results suggest an important link between APP metabolism and the JNK pathway and contribute to shed light on the molecular signalling pathway of this disease indicating JNK as an innovative target for AD therapy.

JNK regulates APP cleavage and degradation in a model of Alzheimer's disease / A. Colombo, A. Bastone, C. Ploia, A. Sclip, M. Salmona, G. Forloni, T. Borsello. - In: NEUROBIOLOGY OF DISEASE. - ISSN 0969-9961. - 33:3(2009 Mar), pp. 518-525.

JNK regulates APP cleavage and degradation in a model of Alzheimer's disease

A. Colombo;T. Borsello
2009-03

Abstract

Secretion of Amyloid-beta peptide (Aβ) circulating oligomers and their aggregate forms derived by processing of beta-amyloid precursor protein (APP) are a key event in Alzheimer's disease (AD). We show that phosphorylation of APP on threonine 668 may play a role in APP metabolism in H4-APPswcell line, a degenerative AD model. We proved that JNK plays a fundamental role in this phosphorylation since its specific inhibition, with the JNK inhibitor peptide (D-JNKI1), induced APP degradation and prevented APP phosphorylation at T668. This results in a significant drop of βAPPs, Aβ fragments and Aβ circulating oligomers. Moreover the D-JNKI1 treatment produced a switch in the APP metabolism, since the peptide reduced the rate of the amyloidogenic processing in favour of the non-amyloidogenic one. All together our results suggest an important link between APP metabolism and the JNK pathway and contribute to shed light on the molecular signalling pathway of this disease indicating JNK as an innovative target for AD therapy.
Alzheimer's disease; amyloid-precursor protein; c-jun n-terminal kinase; D-JNKI1; intracellular signalling; oligomers; phosphorylation; alzheimer disease; amyloid precursor protein secretases; amyloid beta-protein precursor; aspartic acid endopeptidases; cell line, tumor; cell survival; enzyme-linked immunosorbent assay; fluoroimmunoassay; humans; immunoblotting; immunohistochemistry; jnk mitogen-activated protein kinases; map kinase signaling system; mutation; peptide fragments; peptides; phosphorylation; protease nexins; receptors, cell surface; neurology
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/2434/567219
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