Sun Miao-Kun, Alkon Daniel L
Blanchette Rockefeller Neurosciences Institute, Rockville 20850, USA.
J Neurophysiol. 2002 May;87(5):2441-9. doi: 10.1152/jn.00230.2001.
In Alzheimer's disease, the cholinergic damage (reduced neurotransmission) and cognitive impairment occur long before beta-amyloid (Abeta) plaque formation. It has not been established whether the link between soluble Abeta and cholinergic functions contributes to synaptic dysfunction that underlies the cognitive impairment. Here, we report that Abeta(25-35), an active form of Abeta, inhibited long-term synaptic modification that depends on the associative activation of cholinergic and GABAergic inputs when bilaterally injected intracerebroventricularly (icv; 200 microg/site). The Abeta microinjections did not affect single-pulse-evoked glutamatergic and GABAergic synaptic transmission onto the hippocampal CA1 pyramidal cells, while cholinergic intracellular theta; was dramatically reduced by the Abeta(25-35) injection. Spatial memory of the water maze task was also impaired by the bilateral icv Abeta(25-35) injections, while bilateral microinjections of the same dose of Abeta(35-25) was ineffective in affecting the long-term synaptic modification evoked by associative activation of cholinergic and GABAergic inputs, the cholinergic intracellular theta;, or producing memory impairments. Thus restoring the synaptic plasticity involved in this associative activation of cholinergic and GABAergic inputs may offer an important therapeutic target in the treatment of early Abeta-induced memory decline.
在阿尔茨海默病中，胆碱能损伤（神经传递减少）和认知障碍早在β-淀粉样蛋白（Aβ）斑块形成之前就已出现。可溶性Aβ与胆碱能功能之间的联系是否导致了认知障碍所基于的突触功能障碍，目前尚未明确。在此，我们报告，当双侧脑室内注射（icv；200微克/部位）时，Aβ的一种活性形式Aβ（25-35）抑制了依赖胆碱能和GABA能输入联合激活的长期突触修饰。Aβ微量注射并不影响单脉冲诱发的谷氨酸能和GABA能突触传递至海马CA1锥体细胞，而胆碱能细胞内θ波在注射Aβ（25-35）后显著降低。双侧脑室内注射Aβ（25-35）也损害了水迷宫任务的空间记忆，而双侧微量注射相同剂量的Aβ（35-25）对胆碱能和GABA能输入联合激活诱发的长期突触修饰、胆碱能细胞内θ波或产生记忆损伤均无影响。因此，恢复胆碱能和GABA能输入联合激活所涉及的突触可塑性可能为治疗早期Aβ诱导的记忆衰退提供一个重要的治疗靶点。
