Inhibition of JNK/dFOXO pathway and caspases rescues neurological impairments in Drosophila Alzheimer’s disease model

• Published in: Biochemical and biophysical research communications Vol. 419; no. 1; pp. 49 - 53
• Main Authors: Hong, Yoon Ki, Lee, Soojin, Park, Seung Hwan, Lee, Jang Ho, Han, Seung Yeop, Kim, Sang Tae, Kim, Young-Kyoon, Jeon, Songhee, Koo, Byung-Soo, Cho, Kyoung Sang
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 02.03.2012
• Subjects: Alzheimer Disease - enzymology; Alzheimer Disease - pathology; Alzheimer’s disease; Amyloid beta-Peptides - metabolism; Amyloid beta-Peptides - pharmacology; Animals; Anthracenes - pharmacology; Apoptosis; Brain - drug effects; Brain - enzymology; Brain - pathology; Caspases - metabolism; dFOXO; Disease Models, Animal; Drosophila; Drosophila melanogaster - cytology; Drosophila melanogaster - enzymology; Drosophila melanogaster - physiology; Drosophila Proteins - metabolism; Forkhead Transcription Factors - metabolism; Jun-N-terminal kinase; MAP Kinase Kinase 4 - antagonists & inhibitors; MAP Kinase Kinase 4 - metabolism; Neurons - drug effects; Neurons - enzymology; Neurons - pathology; Peptide Fragments - metabolism; Peptide Fragments - pharmacology; Protein Kinase Inhibitors - pharmacology; Signal Transduction; AD; Aβ42; Alzheimer’s disease; dFOXO; JNK; Drosophila; Jun-N-terminal kinase; Apoptosis
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2012.01.122

[Display omitted] ► Aβ42 expression induces apoptosis and reduces survival and locomotion in Drosophila. ► Inhibition of JNK signaling or caspases suppresses the Aβ42-induced impairments. ► Aβ42-induced cell death and neurological phenotypes are dependent on the dFOXO level. ► Oral uptake of the JNK inhibitor rescues the impairments of Aβ42-expressing flies. ► JNK/dFOXO signaling is a major pathway mediating the impairments of the fly AD model. Amyloid-β-42 (Aβ42) has been implicated in the pathogenesis of Alzheimer’s disease (AD). Neuronal Aβ42 expression induces apoptosis and decreases survival and locomotive activity in Drosophila. However, the mechanism by which Aβ42 induces these neuronal impairments is unclear. In this study, we investigated the underlying pathway in theses impairments. JNK activity was increased in Aβ42-expressing brains, and the Aβ42-induced defects were rescued by reducing JNK or caspase activity through genetic modification or pharmacological treatment. In addition, these impairments were restored by Drosophila forkhead box subgroup O (dFOXO) deficiency. These results suggest that the JNK/dFOXO pathway confers a therapeutic potential for AD.