Effects of donepezil on amyloid-beta and synapse density in the Tg2576 mouse model of Alzheimer's disease.
Effects of donepezil on amyloid-beta and synapse density in the Tg2576 mouse model of Alzheimer's disease.
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DOI：
10.1016/j.brainres.2009.09.097
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发表时间：
2009-12-15
期刊：
影响因子：
2.9
通讯作者：
Csernansky, John G.
中科院分区：
文献类型：
--
作者：
Dong, Hongxin;Yuede, Carla M.;Coughlan, Carolyn A.;Murphy, Keely M.;Csernansky, John G.
多奈哌齐是一种乙酰胆碱酯酶抑制剂，已被批准用于治疗阿尔茨海默病（AD）。虽然广泛的研究已经证明了多奈哌齐治疗AD患者的症状疗效，但多奈哌齐对AD过程的影响（如果有的话）尚不清楚。在这项研究中，我们试图确定长期给予多奈哌齐是否会减缓淀粉样斑块沉积或赋予AD小鼠模型神经元保护作用。我们采用定量光镜和电镜观察了长期给药（3 ~ 9月龄，连续给药6个月）多奈哌齐（1、2、4 mg/kg，饮水）对Tg 2576小鼠海马组织中β淀粉样蛋白（Aβ）、斑块沉积、突触蛋白（突触素）和突触密度的影响。与溶媒和较低剂量的多奈哌齐相比，给予4 mg/kg剂量的多奈哌齐可显著降低Tg 2576小鼠研究终点时的脑组织可溶性Aβ 1-40和1-42、Aβ斑块数量和负荷。4 mg/kg多奈哌齐也显著增加Tg 2576小鼠齿状回分子层中的突触密度。然而，在海马中的突触体蛋白阳性终末没有观察到显著的变化。这些结果表明，较高剂量的多奈哌齐可能对Aβ蛋白的组织水平、斑块沉积具有可测量的影响，并且可能预防AD的Tg 2576小鼠模型中的突触丢失。
Donepezil, an acetylcholinesterase inhibitor, is an approved drug for the treatment of Alzheimer's disease (AD). Although extensive studies have demonstrated the symptomatic efficacy of donepezil treatment in patients with AD, the effects of donepezil, if any, on the AD process are not known. In this study, we sought to determine whether long-term administration of donepezil would slow amyloid plaque deposition or confer neuronal protection in a mouse model of AD. We used quantitative light and electron microscopy to investigate the effects of long-term administration (from 3 to 9 months of age for 6 months of treatment) of donepezil (1, 2, 4 mg/kg, in drinking water) on tissue amyloid-β (Aβ) protein, plaque deposition, synaptic protein (synaptophysin) and synapse density in the hippocampus of Tg2576 mice. Administration of the 4 mg/kg dose of donepezil, as compared to vehicle and lower doses of donepezil, significantly reduced brain tissue soluble Aβ 1-40 and 1-42, Aβ plaque number, and burden at the study endpoint in Tg2576 mice. 4mg/kg of donepezil also significantly increased synaptic density in the molecular layer of the dentate gyrus in Tg2576 mice. However, a significant change of the synaptophysin-positive bouton in the hippocampus was not observed. These results suggest that a higher dose of donepezil may have a measurable impact on tissue level of Aβ protein, plaque deposition, and may prevent synapse loss in the Tg2576 mouse model of AD.
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影响因子：
2.4
作者：
Basun, H;Nilsberth, C;Younkin, S
通讯作者：
Younkin, S
DOI：
10.1016/j.brainresprot.2004.09.003
发表时间：
2004-11-01
期刊：
BRAIN RESEARCH PROTOCOLS
影响因子：
--
作者：
Bonthius, DJ;McKim, R;Pantazis, NJ
通讯作者：
Pantazis, NJ
影响因子：
4.2
作者：
Creeley, Catherine E.;Wozniak, David F.;Olney, John W.
通讯作者：
Olney, John W.
影响因子：
25
作者：
Chapman, PF;White, GL;Hsiao, KK
通讯作者：
Hsiao, KK
影响因子：
6.1
作者：
Handattu SP;Garber DW;Monroe CE;van Groen T;Kadish I;Nayyar G;Cao D;Palgunachari MN;Li L;Anantharamaiah GM
通讯作者：
Anantharamaiah GM