RESEARCH HIGHLIGHTS Nature Reviews Neuroscience | AOP, published online 26 November 2014; doi:10.1038/nrn3882
AG I N G
A slow slide in memory exclusively in glia, and amounts increase upon aging, but are decreased in DC0/+ flies compared to agematched wild-type flies. Decreasing dPC expression in old flies ameliorates AMI, while increasing dPC expression in young flies accelerates AMI. To determine the possible link between oxidative damage and dPC in AMI, the authors fed adult wildtype flies a reactive oxygen species (ROS) generating agent. Despite increased heat shock protein 22 (HSP22), which is a marker of oxidative damage, no change in dPC expression was observed. Importantly, memory impairments caused by overexpression of dPC in glia were not accompanied by increases in HSP-22, suggesting that AMI and memory loss due to oxidative damage occur through different mechanisms. How does increased dPC activity cause AMI? Yamazaki et al. show that dPC activity negatively regulates amounts of D-serine, a neuromodulator at the NMDA receptor. D-serine levels decrease with age, but remain high in mutant flies with reduced dPC or PKA activity. In addition, feeding wild-type flies D-serine reverses AMI
caused by overexpression of glial dPC or neuronal DC0. Overall, these data suggest that AMI in Drosophila is caused by reduced NMDA receptor activity rather than oxidative damage. Sian Lewis ORIGINAL RESEARCH PAPER(S) Yamazaki, D. Glial Dysfunction Causes Age-Related Memory Impairment in Drosophila. Neuron http://dx.doi. org/10.1016/j.neuron.2014.09.039 (2014)
AMI and memory loss due to oxidative damage occur through different mechanisms
Jennie Vallis /NPG
Most species, including humans and fruit flies, exhibit age-related memory impairment (AMI). Various causes have been proposed, many of which converge on a mechanism involving cumulative oxidative damage. This hypothesis remains controversial, however. Yamazaki et al. now show that in Drosophila melanogaster, AMI results from reduced NMDA receptor activation caused by age-related alterations in glial activity, and decreased D-serine production. Crucially, this mechanism is independent of oxidative damage. AMI in Drosophila can be detected as a decrease in middle-term olfactory memory [MTM]. Yamazaki et al. previously found that flies with reduced activity of the DC0 gene (DC0/+), which encodes the main catalytic subunit of PKA, have attenuated AMI. However, PKA activity does not increase upon aging, and mechanisms downstream from PKA were unknown. In this study, Yamazaki et al. used preoteomic analysis to identify the Drosophila homologue of pyruvate carboxylase (dPC) as an AMI-causal protein. dPC is found
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