Inhibition of JNK/dFOXO pathway and caspases rescues neurological impairments in Drosophila Alzheimer's disease 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.
Department of Biological Sciences, Konkuk University, Seoul 143-701, Republic of Korea.
Yoon Ki
YK
Hong
Soojin
S
Lee
Seung Hwan
SH
Park
Jang Ho
JH
Lee
Seung Yeop
SY
Han
Sang Tae
ST
Kim
Young-Kyoon
YK
Kim
Songhee
S
Jeon
Byung-Soo
BS
Koo
Kyoung Sang
KS
Cho
D000544:Alzheimer Disease / Q000201:enzymology* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D000873:Anthracenes / Q000494:pharmacology; D017209:Apoptosis; D001921:Brain / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D020169:Caspases / Q000378:metabolism*; D004195:Disease Models, Animal; D029721:Drosophila Proteins / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000166:cytology / Q000201:enzymology* / Q000502:physiology; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D048670:MAP Kinase Kinase 4 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D010446:Peptide Fragments / Q000378:metabolism* / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D015398:Signal Transduction
D016229:Amyloid beta-Peptides; D000873:Anthracenes; D029721:Drosophila Proteins; C477334:FOXO protein, Drosophila; D051858:Forkhead Transcription Factors; D010446:Peptide Fragments; D047428:Protein Kinase Inhibitors; C075222:amyloid beta-protein (1-42); C432165:pyrazolanthrone; D048670:MAP Kinase Kinase 4; D020169:Caspases