Chemical genetic activation of the cholinergic basal forebrain hippocampal circuit rescues memory loss in Alzheimer's disease.
Chemical genetic activation of the cholinergic basal forebrain hippocampal circuit rescues memory loss in Alzheimer's disease.
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胆碱能基底前脑海马回路的化学基因激活可挽救阿尔茨海默病的记忆丧失
DOI：
10.1186/s13195-022-00994-w
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发表时间：
2022-04-13
期刊：
影响因子：
--
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中科院分区：
文献类型：
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从基底前脑到海马体的胆碱能回路的退化导致阿尔茨海默病（AD）患者的记忆丧失。然而，乙酰胆碱（Ach）循环与AD早期记忆衰退之间的内在关系目前尚不清楚。在这里，我们利用APP/PS1小鼠模型研究胆碱能回路激活的机制及其对学习和记忆的影响。采用新颖的目标识别和Morris水迷宫测试来测量学习记忆功能。应用磁共振波谱（MRS）成像纵向跟踪2、4、6、8月龄APP/PS1小鼠神经化学代谢的变化。采用尼氏染色、免疫组化、硫黄素S染色检测神经元数量和Aβ斑块沉积。然后，我们采用一种化学发生策略，选择性地激活从基底前脑内侧间隔核（MS）和对角带核（VDB）的垂直分支到海马的胆碱能回路。采用MRS和免疫印迹技术分别测定神经化学代谢水平和胆碱能相关蛋白。我们发现，4、6和8月龄APP/PS1小鼠基底前脑胆碱（Cho）水平明显高于其他脑区，其随海马n -乙酰天冬氨酸（NAA）水平下降而下降，并伴有记忆缺陷。在病理方面，我们观察到6月龄和8月龄APP/PS1小鼠大脑皮层和海马的Aβ斑块沉积逐渐加重，而基底前脑未检测到Aβ沉积。6月龄时基底前脑胆碱乙酰转移酶（ChAT）活性下降，8月龄时基底前脑胆碱能神经元丧失。此外，利用化学遗传学激活从MS和VDB到海马体的胆碱能回路能够改善APP/PS1小鼠的学习和减少记忆障碍。同样，基底前脑的Cho水平;海马NAA，基底前脑ChAT和囊泡性乙酰胆碱转运蛋白（vAchT）的表达；海马毒蕈碱乙酰胆碱受体2 （CHRM2）均升高。这些发现表明胆碱能回路的神经化学物质Cho和NAA可以作为AD早期诊断的生物标志物。此外，利用化学遗传学驱动的胆碱能回路的Ach循环活性可以减轻APP/PS1小鼠的记忆损伤。在线版本包含补充材料，可在10.1186/s13195-022-00994-w获得。
The degeneration of the cholinergic circuit from the basal forebrain to the hippocampus contributes to memory loss in patients suffering from Alzheimer’s disease (AD). However, the internal relationships between the acetylcholine (Ach) cycle and memory decline during the early stages of AD currently remain unknown. Here, we investigate the mechanisms underlying the activation of the cholinergic circuit and its impact on learning and memory using APP/PS1 mice models. Novel object recognition and Morris water maze tests were used to measure learning and memory function. Magnetic resonance spectrum (MRS) imaging was applied to longitudinally track changes in neurochemical metabolism in APP/PS1 mice aged 2, 4, 6, and 8 months. The number of neurons and the deposition of Aβ plaques were measured using Nissl, immunohistochemistry, and Thioflavin S staining. We then employed a chemogenetic strategy to selectively activate the cholinergic circuit from the medial septal nucleus (MS) and the vertical limb of the diagonal band nucleus (VDB) on the basal forebrain to the hippocampus. MRS and immunoblotting techniques were used to measure the neurochemical metabolism levels and cholinergic-related proteins, respectively. We found that the levels of choline (Cho) in the basal forebrain were markedly higher compared to other brain regions and that its decrease along with N-acetyl aspartate (NAA) levels in the hippocampus was accompanied by memory deficits in APP/PS1 mice aged 4, 6, and 8 months. In terms of pathology, we observed that the deposition of Aβ plaques gradually aggravated throughout the cerebral cortex and hippocampus in APP/PS1 mice aged 6 and 8 months, while no Aβ deposition was detected in the basal forebrain. In contrast, the activity of choline acetyltransferase (ChAT) enzyme in the basal forebrain was decreased at 6 months of age and the cholinergic neurons were lost in the basal forebrain at 8 months of age. In addition, the activation of the cholinergic circuit from the MS and VDB to the hippocampus using chemical genetics is able to improve learning and reduce memory impairment in APP/PS1 mice. Similarly, the levels of Cho in the basal forebrain; NAA in the hippocampus, as well as the expression of ChAT and vesicular acetylcholine transporter (vAchT) in the basal forebrain; and muscarinic acetylcholine receptor 2 (CHRM2) in the hippocampus all increased. These findings demonstrate that the neurochemical Cho and NAA of the cholinergic circuit can be used as biomarkers to enable the early diagnosis of AD. In addition, memory impairment in APP/PS1 mice can be attenuated using chemical genetics-driven Ach cycle activity of the cholinergic circuit. The online version contains supplementary material available at 10.1186/s13195-022-00994-w.
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DOI：
10.1016/s0140-6736(20)32205-4
发表时间：
2021-04-24
期刊：
Lancet (London, England)
影响因子：
--
作者：
Scheltens P;De Strooper B;Kivipelto M;Holstege H;Chételat G;Teunissen CE;Cummings J;van der Flier WM
通讯作者：
van der Flier WM
影响因子：
4.2
作者：
Grothe M;Heinsen H;Teipel S
通讯作者：
Teipel S
DOI：
10.1097/nen.0b013e318288a8dd
发表时间：
2013-04-01
影响因子：
3.2
作者：
Jose Ramos-Rodriguez, Juan;Pacheco-Herrero, Mar;Garcia-Alloza, Monica
通讯作者：
Garcia-Alloza, Monica
影响因子：
16.2
作者：
Gu Z;Yakel JL
通讯作者：
Yakel JL
胆碱能系统全脑图谱的生成和基底前脑胆碱能神经元的介观投影组分析。
DOI：
10.1073/pnas.1703601115
发表时间：
2018-01-09
影响因子：
11.1
作者：
Li, Xiangning;Yu, Bin;Qiu, Zilong
通讯作者：
Qiu, Zilong