Genetic Dissection of Age-related Memory Impairment

年龄相关记忆障碍的基因剖析

• 批准号: 16300107
• 负责人: SAITOE Minoru
• 金额: $ 9.47万
• 依托单位: Tokyo Metropolitan Organization for Medical Research
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2004
• 资助国家: 日本
• 起止时间: 2004 至 2006
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-16300107/
• 关键词: Learning and Memory; PKA; Aging; Mutant; Molecular Mechanism; 遺伝子; ショウジョウバエ; 学主記憶; Learning and Memory; PKA; Aging; Mutant; Molecular Mechanism; 遺伝子; ショウジョウバエ; 学主記憶

Although it is widely known that aging is associated with memory loss, the specific molecular mechanisms that contribute to age-related memory impairment (AMI) are unknown, because of a lack of AMI-specific mutants. Previously, we determined that Drosophila aging specifically impairs memory phase depending on amnesiac (amn), gene encoding putative neuropeptides, and hypothesized that signaling downstream of amn leads to AMI. In this current project, we extend this work by screening for mutants with altered AMI onset and identifying that heterozygous mutations in DC0, the gene encoding the catalytic subunit of PKA, delay AMI more than two fold without affecting memory at young ages. Furthermore, our identified DC0 mutants do not show any increases in longevity, demonstrating that AMI can be dissociated from organismal aging. Given the identification of DC0, we demonstrate that PKA activity in the mushroom bodies (MBs), structures important in memory formation, causes AMI and AMI onset can be controlled by altering cAMP/PKA signaling activity in the MBs. Notably, putative neuropeptides encoded by amn are proposed to regulate cAMP level, and DPM cells expressing amn innervate MBs. In addition, amn mutants do not show further memory decay upon aging. We show here that both amn-dependent memory and AMI are restored in amn ; DC0/+ double mutants. These results suggest that cAMP/PKA signaling in the MBs is a downstream of amn and leads to AMI upon aging.

尽管众所周知，衰老与记忆丧失有关，但由于缺乏AMI特异性突变体，导致与年龄相关的记忆障碍（AMI）的特定分子机制是未知的。以前，我们确定果蝇的衰老特异性损害了记忆阶段，具体取决于失忆症（AMN），编码假定神经肽的基因，并假设AMN下游的信号导致AMI。在当前的项目中，我们通过筛选改变AMI发作改变的突变体并确定DC0中的杂合突变，该突变是编码PKA的催化亚基的杂合突变，延迟AMI超过两个倍数，而不会影响年轻年龄的记忆。此外，我们确定的DC0突变体没有显示出寿命的任何增加，这表明AMI可以与有机体衰老分离。鉴于DC0的识别，我们证明了蘑菇体（MBS）中的PKA活性，在记忆形成中很重要的结构可以通过改变MBS中的CAMP/PKA信号传导活性来控制AMI和AMI的原因。值得注意的是，提出了由AMN编码的推定神经肽来调节cAMP水平，而表达AMN的DPM细胞支配MBS。此外，AMN突变体在衰老时不会显示出进一步的记忆衰减。我们在这里表明，在AMN中恢复了依赖AMN的记忆和AMI。 DC0/+双突变体。这些结果表明，MBS中的CAMP/PKA信号是AMN的下游，并在衰老后导致AMI。