Central activation of PPAR-gamma ameliorates diabetes induced cognitive dysfunction and improves BDNF expression
Central activation of PPAR-gamma ameliorates diabetes induced cognitive dysfunction and improves BDNF expression
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DOI：
10.1016/j.neurobiolaging.2014.09.028
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发表时间：
2015-03-01
影响因子：
4.2
通讯作者：
Amin, Rajesh H.
中科院分区：
文献类型：
--
作者：
Kariharan, Thiruchelvam;Nanayakkara, Gayani;Amin, Rajesh H.
糖尿病和阿尔茨海默病在认知缺陷方面有共同的病理联系。核受体的药理学激动剂，过氧化物酶体增殖物激活受体γ（PPAR γ），即罗格列酮（rosi），是改善阿尔茨海默病记忆的胰岛素增敏剂。然而，还没有研究过海马中通过PPAR γ改善记忆的直接分子信号传导靶点。我们比较了口服与脑室内（ICV）给药rosi对2型糖尿病（db/db）小鼠记忆和突触可塑性变化的影响。用rosi（ICV）处理的Db/db小鼠显示出记忆、长时程增强和强直后增强的显著改善，但没有改善外周胰岛素敏感性。基因和蛋白质分析显示，增加脑源性神经营养因子（BDNF）在db/db小鼠与rosi（ICV）治疗。通过荧光素酶测定确定的外显子IX的转录激活证实了BDNF启动子活性的PPAR γ调节。瞬时转染海马神经元细胞中的组成型激活的过氧化物酶体增殖物激活受体γ质粒诱导增加BDNF，AMPA和NMDA受体表达和棘形成。本研究的发现暗示了一种新的PPAR γ-BDNF分子信号传导机制作为认知障碍的潜在治疗靶点。(C)2015 Elsevier Inc. All rights reserved.
Diabetes and Alzheimer's disease share pathologic links toward cognitive deficits. Pharmacologic agonist of the nuclear receptor, peroxisomal proliferator-activating receptor gamma (PPAR gamma), that is, rosiglitazone (rosi), are insulin sensitizing agents that improve memory in Alzheimer's disease. However, direct molecular signaling targets that improve memory by PPAR gamma in the hippocampus have not been investigated. We compared outcomes from oral versus intracerebroventricular (ICV) administration of rosi on memory and changes in synaptic plasticity in type 2 diabetic (db/db) mice. Db/db mice treated with rosi (ICV) showed significant improvement in memory, long-term potentiation, and post-tetanic potentiation but did not improve peripheral insulin sensitivity. Gene and protein analysis revealed increased brainderived neurotrophic factor (BDNF) in db/db mice treated with rosi (ICV). Transcriptional activation of exon IX as determined by luciferase assays confirmed PPAR gamma regulation of BDNF promoter activity. Transient transfection of constitutively active PPAR gamma plasmid in hippocampal neuronal cells induced increased BDNF, AMPA, and NMDA receptors expression and spine formation. Findings from the present study implicate a novel PPAR gamma-BDNF molecular signaling mechanism as a potential therapeutic target for cognitive impairment. (C) 2015 Elsevier Inc. All rights reserved.