Chronic stress exacerbates tau pathology, neurodegeneration, and cognitive performance through a corticotropin-releasing factor receptor-dependent mechanism in a transgenic mouse model of tauopathy.
Chronic stress exacerbates tau pathology, neurodegeneration, and cognitive performance through a corticotropin-releasing factor receptor-dependent mechanism in a transgenic mouse model of tauopathy.
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慢性应激加剧了tau病理学，神经退行性变化和认知性能，通过伴皮质激素释放因子受体受体依赖性机制在tauopathy的转基因小鼠模型中。
DOI：
10.1523/jneurosci.3836-11.2011
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发表时间：
2011-10-05
期刊：
影响因子：
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通讯作者：
Trojanowski JQ
中科院分区：
文献类型：
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作者：
Carroll JC;Iba M;Bangasser DA;Valentino RJ;James MJ;Brunden KR;Lee VM;Trojanowski JQ
由于阿尔茨海默病(AD)患者存在下丘脑-垂体-肾上腺(HPA)轴的过度激活，应激性神经介质调节失调可能在AD的病理生理机制中起一定作用。然而，应激对tau磷酸化的影响还不清楚，皮质酮和促肾上腺皮质激素释放因子在Aβ和tau病理中的关系也不清楚。因此，我们首先建立了一种慢性应激在Tg2576小鼠体内加剧Aβ蓄积的模型，然后将这种应激范式扩展到带有P301S突变(PS19)的tau转基因小鼠模型，该突变表现为tau过度磷酸化、不溶性tau包涵体和神经退行性变。我们首次表明，Tg2576和PS19小鼠在非应激状态下都表现出更高的HPA应力分布。在Tg2576小鼠中，与非应激小鼠相比，一个月的束缚/隔离(RI)应激增加了Aβ水平，抑制了小胶质细胞的激活，并恶化了空间记忆和恐惧记忆。在PS19小鼠中，RI应激促进tau过度磷酸化、不溶性tau聚集、神经变性和恐惧记忆损伤。这些效应不能被长期给予皮质酮模拟，但可以通过预先给予CRF受体1型(CRF1)拮抗剂来阻止。与野生型相比，过度表达CRF的小鼠增加了过度磷酸化的tau，这进一步支持了CRF1依赖机制的作用。综上所述，这些结果提示HPA在AD神经发病机制中的失调，并提示长期应激可能会增加Aβ和tau的过度磷酸化。这些研究还表明CRF与AD的病理生理学有关，并提示对这种神经肽的药理操作可能是一种潜在的AD治疗策略。
Since over-activation of the hypothalamic-pituitary-adrenal (HPA) axis occurs in Alzheimer’s disease (AD), dysregulation of stress neuromediators may play a mechanistic role in the pathophysiology of AD. However, the effects of stress on tau phosphorylation are poorly understood and the relationship between corticosterone and corticotropin-releasing factor (CRF) on both Aβ and tau pathology remain unclear. Therefore, we first established a model of chronic stress which exacerbates Aβ accumulation in Tg2576 mice and then extended this stress paradigm to a tau transgenic mouse model with the P301S mutation (PS19) which displays tau hyperphosphorylation, insoluble tau inclusions and neurodegeneration. We show for the first time that both Tg2576 and PS19 mice demonstrate a heightened HPA stress profile in the unstressed state. In Tg2576 mice, one month of restraint/isolation (RI) stress increased Aβ levels, suppressed microglial activation, and worsened spatial and fear memory compared to non-stressed mice. In PS19 mice, RI stress promoted tau hyperphosphorylation, insoluble tau aggregation, neurodegeneration and fear-memory impairments. These effects were not mimicked by chronic corticosterone administration but were prevented by pre-stress administration of a CRF receptor type 1 (CRF1) antagonist. The role for a CRF1-dependent mechanism was further supported by the finding that mice over-expressing CRF had increased hyperphosphorylated tau compared to wildtype littermates. Together, these results implicate HPA dysregulation in AD neuropathogenesis and suggest that prolonged stress may increase Aβ and tau hyperphosphorylation. These studies also implicate CRF in AD pathophysiology and suggest that pharmacological manipulation of this neuropeptide may be a potential therapeutic strategy for AD.