Altered longevity-assurance activity of p53:p44 in the mouse causes memory loss, neurodegeneration and premature death.
Altered longevity-assurance activity of p53:p44 in the mouse causes memory loss, neurodegeneration and premature death.
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DOI：
10.1111/j.1474-9726.2010.00547.x
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发表时间：
2010-04
期刊：
影响因子：
7.8
通讯作者：
Puglielli L
中科院分区：
文献类型：
--
作者：
Pehar M;O'Riordan KJ;Burns-Cusato M;Andrzejewski ME;del Alcazar CG;Burger C;Scrable H;Puglielli L
肿瘤抑制因子p53的长寿保证活性取决于Δ 40 p53（p44）的水平，Δ 40 p53（p44）是p53基因的一种短的和天然存在的同种型。因此，增加小鼠中p44的剂量会导致加速衰老和缩短寿命。在这里，我们表明，小鼠纯合子的转基因编码p44（p44+/+）显示认知能力下降和突触损伤的生命早期。突触缺陷归因于胰岛素样生长因子1受体（IGF-1 R）信号转导的过度激活和微管结合蛋白tau的代谢改变。事实上，他们被Igf 1 r或Mapt单倍不足所拯救。当表达人类或“人源化”形式的淀粉样前体蛋白（APP）时，p44+/+动物的大脑记忆形成和恢复区域发生选择性变性，并过早死亡。从机制上讲，神经退行性变是由paraptosis和自噬样细胞死亡引起的。这些结果表明，p53：p44的长寿保证活性改变通过影响IGF-1 R信号传导导致记忆丧失和神经退行性变。重要的是，Igf 1 r单倍不足也能够纠正APP 695/swe小鼠（阿尔茨海默病模型）的突触缺陷。
The longevity-assurance activity of the tumor suppressor p53 depends on the levels of Δ40p53 (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 APP695/swe mice, a model of Alzheimer’s disease.
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