Tokyo Metropolitan Institute for Neuroscience, Fuchu, Tokyo 183-8526, Japan.
J Neurosci. 2010 Nov 17;30(46):15573-7. doi: 10.1523/JNEUROSCI.3229-10.2010.
Age-related memory impairment (AMI) is a critical and debilitating phenotype of brain aging, but its underlying molecular mechanisms are largely unknown. In Drosophila, AMI is highly correlated with PKA activity in the mushroom bodies, neural centers essential for forming associative olfactory memories. Heterozygous mutations in DC0 (DC0/+), which encodes the major catalytic subunit of PKA (PKAc), significantly suppress AMI, while overexpression of a DC0 transgene (DC0(+)) impairs memory and occludes AMI. PKA activity does not increase upon aging, and it is not clear whether AMI is caused by continual PKA activity throughout aging or by an acute increase in PKA signaling at old ages. Likewise, it is not clear whether AMI can be ameliorated by acute interventions at old ages or whether continuous intervention throughout aging is necessary. We show here that an acute increase in PKA activity at old ages is sufficient to restore normal AMI in DC0/+ flies. Conversely, acute expression of a PKA inhibitory peptide at old ages is sufficient to reverse AMI in a wild-type background. These results indicate that AMI in Drosophila is caused by an age-dependent change in PKA-dependent signaling that can be reversed by acute interventions at old ages.
年龄相关性记忆障碍（AMI）是大脑衰老的一种关键且使人虚弱的表型，但其潜在的分子机制在很大程度上尚不清楚。在果蝇中，AMI 与蘑菇体中的 PKA 活性高度相关，蘑菇体是形成嗅觉联想记忆所必需的神经中枢。PKA（PKAc）主要催化亚基编码基因 DC0 的杂合突变（DC0/+）显著抑制 AMI，而过表达 DC0 转基因（DC0(+））则损害记忆并阻断 AMI。PKA 活性不会随年龄增长而增加，目前尚不清楚 AMI 是由整个衰老过程中的持续 PKA 活性引起的，还是由老年时 PKA 信号的急性增加引起的。同样，目前尚不清楚 AMI 是否可以通过老年时的急性干预来改善，或者是否需要在整个衰老过程中进行持续干预。我们在这里表明，老年时 PKA 活性的急性增加足以恢复 DC0/+ 果蝇的正常 AMI。相反，老年时急性表达 PKA 抑制肽足以在野生型背景下逆转 AMI。这些结果表明，果蝇中的 AMI 是由 PKA 依赖性信号的年龄依赖性变化引起的，可以通过老年时的急性干预来逆转。
