7,8-Dihydroxyflavone, a small molecule TrkB agonist, improves spatial memory and increases thin spine density in a mouse model of Alzheimer disease-like neuronal loss.
7,8-Dihydroxyflavone, a small molecule TrkB agonist, improves spatial memory and increases thin spine density in a mouse model of Alzheimer disease-like neuronal loss.
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DOI：
10.1371/journal.pone.0091453
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
LaFerla FM
中科院分区：
文献类型：
--
作者：
Castello NA;Nguyen MH;Tran JD;Cheng D;Green KN;LaFerla FM
增强BDNF/TrkB信号转导已被证明是逆转阿尔茨海默病（AD）临床前模型中认知缺陷的有前途的策略。尽管这些研究强调了靶向BDNF/TrkB信号传导的潜力，但这种策略尚未在发展与AD中认知下降最密切相关的疾病特征的模型中进行测试：严重的突触和神经元损失。在本研究中，我们研究了TrkB激动剂7，8-二羟基黄酮（DHF）在CaM/Tet-DTA小鼠中的影响，这是一种海马和皮质严重神经元丢失的诱导模型。通过水迷宫测定，全身7，8-DHF治疗显著改善了损伤小鼠的空间记忆。GFP标记的CaM/Tet-DTA小鼠神经元的分析表明，7，8-DHF诱导损伤小鼠CA 1中薄棘密度的显着和选择性增加，而不影响蘑菇状或棘状突起。这些发现表明，用7，8-DHF慢性上调TrkB信号传导可能是改善AD功能的有效和实用的策略，即使在发生大量神经元损失之后。
Augmenting BDNF/TrkB signaling has been demonstrated to be a promising strategy for reversing cognitive deficits in preclinical models of Alzheimer disease (AD). Although these studies highlight the potential of targeting BDNF/TrkB signaling, this strategy has not yet been tested in a model that develops the disease features that are most closely associated with cognitive decline in AD: severe synaptic and neuronal loss. In the present study, we investigated the impact of 7,8-dihydroxyflavone (DHF), a TrkB agonist, in CaM/Tet-DTA mice, an inducible model of severe neuronal loss in the hippocampus and cortex. Systemic 7,8-DHF treatment significantly improved spatial memory in lesioned mice, as measured by water maze. Analysis of GFP-labeled neurons in CaM/Tet-DTA mice revealed that 7,8-DHF induced a significant and selective increase in the density of thin spines in CA1 of lesioned mice, without affecting mushroom or stubby spines. These findings suggest chronic upregulation of TrkB signaling with 7,8-DHF may be an effective and practical strategy for improving function in AD, even after substantial neuronal loss has occurred.
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影响因子：
82.9
作者：
Nagahara AH;Merrill DA;Coppola G;Tsukada S;Schroeder BE;Shaked GM;Wang L;Blesch A;Kim A;Conner JM;Rockenstein E;Chao MV;Koo EH;Geschwind D;Masliah E;Chiba AA;Tuszynski MH
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