Restoring polyamines protects from age-induced memory impairment in an autophagy-dependent manner
Restoring polyamines protects from age-induced memory impairment in an autophagy-dependent manner
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DOI：
10.1038/nn.3512
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发表时间：
2013-10-01
影响因子：
25
通讯作者：
Sigrist, Stephan J.
中科院分区：
文献类型：
--
作者：
Gupta, Varun K.;Scheunemann, Lisa;Sigrist, Stephan J.
已知在几种生物体中发生了依赖性记忆障碍，包括果蝇、小鼠和人类。然而，这些损伤背后的基本细胞机制仍然知之甚少，有效地阻碍了治疗这种疾病的药理学策略的发展。多胺是人类大脑中随着年龄增长而减少的物质之一。我们发现，多胺（亚精胺，腐胺）的水平下降，在老化的果蝇，伴随着记忆能力下降。单纯的亚精胺喂养不仅恢复少年多胺水平，但也抑制年龄引起的记忆障碍。鸟氨酸脱羧酶-1，从头多胺合成的限速酶，也保护嗅觉记忆在老年苍蝇时，专门表达在凯尼恩细胞，这是至关重要的嗅觉记忆的形成。亚精胺喂养的果蝇表现出增强的自噬（细胞自我消化的一种形式），自噬机制中的遗传缺陷阻止了亚精胺介导的记忆障碍的拯救。我们的研究结果表明，自噬是至关重要的抑制记忆障碍亚精胺和多胺，这是内源性的，是药物干预的候选人。
Age-dependent memory impairment is known to occur in several organisms, including Drosophila, mouse and human. However, the fundamental cellular mechanisms that underlie these impairments are still poorly understood, effectively hampering the development of pharmacological strategies to treat the condition. Polyamines are among the substances found to decrease with age in the human brain. We found that levels of polyamines (spermidine, putrescine) decreased in aging fruit flies, concomitant with declining memory abilities. Simple spermidine feeding not only restored juvenile polyamine levels, but also suppressed age-induced memory impairment. Ornithine decarboxylase-1, the rate-limiting enzyme for de novo polyamine synthesis, also protected olfactory memories in aged flies when expressed specifically in Kenyon cells, which are crucial for olfactory memory formation. Spermidine-fed flies showed enhanced autophagy (a form of cellular self-digestion), and genetic deficits in the autophagic machinery prevented spermidine-mediated rescue of memory impairments. Our findings indicate that autophagy is critical for suppression of memory impairments by spermidine and that polyamines, which are endogenously present, are candidates for pharmacological intervention.