Department of Medicine, University of Wisconsin-Madison, WI 53705, USA.
Aging Cell. 2010 Apr;9(2):174-90. doi: 10.1111/j.1474-9726.2010.00547.x.
The longevity-assurance activity of the tumor suppressor p53 depends on the levels of Delta40p53 (p44), a short and naturally occurring isoform of the p53 gene. As such, increased dosage of p44 in the mouse leads to accelerated aging and short lifespan. Here we show that mice homozygous for a transgene encoding p44 (p44(+/+)) display cognitive decline and synaptic impairment early in life. The synaptic deficits are attributed to hyperactivation of insulin-like growth factor 1 receptor (IGF-1R) signaling and altered metabolism of the microtubule-binding protein tau. In fact, they were rescued by either Igf1r or Mapt haploinsufficiency. When expressing a human or a 'humanized' form of the amyloid precursor protein (APP), p44(+/+) animals developed a selective degeneration of memory-forming and -retrieving areas of the brain, and died prematurely. Mechanistically, the neurodegeneration was caused by both paraptosis- and autophagy-like cell deaths. These results indicate that altered longevity-assurance activity of p53:p44 causes memory loss and neurodegeneration by affecting IGF-1R signaling. Importantly, Igf1r haploinsufficiency was also able to correct the synaptic deficits of APP(695/swe) mice, a model of Alzheimer's disease.
肿瘤抑制因子 p53 的长寿保障活性取决于 Delta40p53（p44）的水平，p44 是 p53 基因的一种短的天然存在的异构体。因此，在小鼠中增加 p44 的剂量会导致衰老加速和寿命缩短。在这里，我们发现编码 p44 的转基因纯合小鼠（p44(+/+)）在生命早期表现出认知能力下降和突触损伤。突触缺陷归因于胰岛素样生长因子 1 受体 (IGF-1R) 信号的过度激活和微管结合蛋白 tau 的代谢改变。事实上，IGF-1R 或 Mapt 杂合不足可以挽救这些缺陷。当表达人类或“人源化”形式的淀粉样前体蛋白 (APP) 时，p44(+/+)动物会出现记忆形成和检索区域的选择性退化，并过早死亡。从机制上讲，神经退行性变是由副凋亡和自噬样细胞死亡引起的。这些结果表明，p53:p44 的长寿保障活性改变通过影响 IGF-1R 信号导致记忆丧失和神经退行性变。重要的是，IGF-1R 杂合不足也能够纠正阿尔茨海默病模型 APP(695/swe)小鼠的突触缺陷。
