PI3 kinase signaling is involved in Abeta-induced memory loss in Drosophila.
Multiple intracellular signals are altered in Alzheimer's disease brain tissues, including the PI3K/Akt pathway. However, the pathological relevance of such alterations is poorly understood. In vitro studies yield results that seem to be consistent with the conventional perception in which an up-regulation of the cell survival pathway, PI3K pathway, is protective in Alzheimer's disease pathogenesis. The current in vivo genetic approach, however, reveals that inhibition of the PI3K pathway leads to rescuing of the beta-amyloid peptide (Abeta)-induced memory loss in the Drosophila brain. We began our inquiry into the molecular basis of this memory loss by studying Abeta42-induced enhancement of long-term depression. We found that long-term depression is restored to a normal level through inhibition of PI3K activity. Abeta42-induced PI3K hyperactivity is directly confirmed by immunostaining of the PI3K phosphorylation targets, phospholipids. Such observations lead to the following demonstration that Abeta42-induced memory loss can be rescued through genetic silencing or pharmacological inhibition of PI3K functions. Our data suggest that Abeta42 stimulates PI3K, which in turn causes memory loss in association with an increase in accumulation of Abeta42 aggregates.
Chiang
Hsueh-Cheng
HC
Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.
Wang
Lei
L
Xie
Zuolei
Z
Yau
Alice
A
Zhong
Yi
Y
D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D030801:Animals, Genetically Modified; D004195:Disease Models, Animal; D004331:Drosophila melanogaster / Q000502:physiology*; D004594:Electrophysiology; D007858:Learning; D008055:Lipids / Q000737:chemistry; D008568:Memory; D008569:Memory Disorders / Q000378:metabolism*; D008954:Models, Biological; D008957:Models, Genetic; D019636:Neurodegenerative Diseases / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation; D012903:Smell
D016229:Amyloid beta-Peptides; D008055:Lipids; D019869:Phosphatidylinositol 3-Kinases