Amyloid β-peptide inhibition of the PKA/CREB pathway and long-term potentiation:: Reversibility by drugs that enhance cAMP signaling
Amyloid β-peptide inhibition of the PKA/CREB pathway and long-term potentiation:: Reversibility by drugs that enhance cAMP signaling
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DOI：
10.1073/pnas.172504199
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发表时间：
2002-10-01
影响因子：
11.1
通讯作者：
Shelanski, M
中科院分区：
文献类型：
--
作者：
Vitolo, OV;Sant'Angelo, A;Shelanski, M
海马功能的变化似乎是阿尔茨海默病（AD）认知障碍的关键。尽管AD和AD动物模型中的突触最终丢失，但空间记忆缺陷和长时程增强（LTP）抑制先于模型中的形态学改变，表明该疾病的早期生化变化。在这里报道的研究中，我们证明了淀粉样β肽（Abeta）处理培养的海马神经元导致蛋白激酶A（PKA）的失活和其调节亚基PKAIIalpha的持续存在。与此相一致，CREB磷酸化响应谷氨酸减少，并通过rolipram逆转减少，rolipram是一种磷酸二酯酶抑制剂，其升高cAMP并导致PKA催化和调节亚基的解离。这可能是一个类似的机制下的Abeta抑制LTP，因为咯利普兰和毛喉素，代理人，加强cAMP信号通路，可以逆转这种抑制。这种逆转被PKA抑制剂H89阻断。这些观察结果表明，Abeta直接作用于参与形成晚期LTIP的途径，并且增强cAMP/PKA/CREB信号传导途径的药物具有治疗AD的潜力。
Changes in hippocampal function seem critical for cognitive impairment in Alzheimer's disease (AD). Although there is eventual loss of synapses in both AD and animal models of AD, deficits in spatial memory and inhibition of long-term potentiation (LTP) precede morphological alterations in the models, suggesting earlier biochemical changes in the disease. In the studies reported here we demonstrate that amyloid beta-peptide (Abeta) treatment of cultured hippocampal neurons leads to the inactivation of protein kinase A (PKA) and persistence of its regulatory subunit PKAIIalpha. Consistent with this, CREB phosphorylation in response to glutamate is decreased, and the decrease is reversed by rolipram, a phosphodiesterase inhibitor that raises cAMP and leads to the dissociation of the PKA catalytic and regulatory subunits. It is likely that a similar mechanism underlies Abeta inhibition of LTP, because rolipram and forskolin, agents that enhance the cAMP-signaling pathway, can reverse this inhibition. This reversal is blocked by H89, an inhibitor of PKA. These observations suggest that Abeta acts directly on the pathways involved in the formation of late LTIP and agents that enhance the cAMP/PKA/CREB-signaling pathway have potential for the treatment of AD.