Persistent improvement in synaptic and cognitive functions in an Alzheimer mouse model after rolipram treatment
Persistent improvement in synaptic and cognitive functions in an Alzheimer mouse model after rolipram treatment
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DOI：
10.1172/jci200422831
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发表时间：
2004-12-01
影响因子：
15.9
通讯作者：
Arancio, O
中科院分区：
文献类型：
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作者：
Gong, B;Vitolo, OV;Arancio, O
有证据表明，阿尔茨海默病（AD）始于突触功能紊乱，部分原因是淀粉样蛋白β -肽1-42 （Abeta42）水平升高。淀粉样蛋白前体蛋白（AA替代K670N，M671L）和早老素-1 （AA替代M146V）双转基因小鼠均可再现突触和认知缺陷。在这里，我们证明用磷酸二酯酶4抑制剂罗利普兰短暂治疗可以改善双转基因小鼠的长期增强（LTP）和上下文学习缺陷。最重要的是，这种有益效果可以延长到服药期间之后。一个疗程的罗利普兰长期全身治疗在治疗结束后至少2个月改善LTP和基础突触传递以及工作、参考和联想记忆缺陷。这种保护作用可能是由于激活cAMP依赖性蛋白激酶(PKA)/cAMP调节元件结合蛋白（CREB）信号通路，通过改变基因表达来稳定突触回路，使突触更能抵抗Abeta造成的伤害。因此，增强cAMP/PKA/CREB通路的药物具有治疗AD和其他与Abeta42水平升高相关的疾病的潜力。
Evidence suggests that Alzheimer disease (AD) begins as a disorder of synaptic function, caused in part by increased levels of amyloid beta-peptide 1-42 (Abeta42). Both synaptic and cognitive deficits are reproduced in mice double transgenic for amyloid precursor protein (AA substitution K670N,M671L) and presenilin-1 (AA substitution M146V). Here we demonstrate that brief treatment with the phosphodiesterase 4 inhibitor rolipram ameliorates deficits in both long-term potentiation (LTP) and contextual learning in the double-transgenic mice. Most importantly, this beneficial effect can be extended beyond the duration of the administration. One course of long-term systemic treatment with rolipram improves LTP and basal synaptic transmission as well as working, reference, and associative memory deficits for at least 2 months after the end of the treatment. This protective effect is possibly due to stabilization of synaptic circuitry via alterations in gene expression by activation of the cAMP-dependent protein kinase (PKA)/cAMP regulatory element-binding protein (CREB) signaling pathway that make the synapses more resistant to the insult inflicted by Abeta. Thus, agents that enhance the cAMP/PKA/CREB pathway have potential for the treatment of AD and other diseases associated with elevated Abeta42 levels.