Kariharan Thiruchelvam, Nanayakkara Gayani, Parameshwaran Kodeeswaran, Bagasrawala Inseyah, Ahuja Manuj, Abdel-Rahman Engy, Amin Arin T, Dhanasekaran Murali, Suppiramaniam Vishnu, Amin Rajesh H
Department of Drug Discovery and Development, Harrison School of Pharmacy, Auburn University, Auburn, AL, USA.
Department of Drug Discovery and Development, Harrison School of Pharmacy, Auburn University, Auburn, AL, USA.
Neurobiol Aging. 2015 Mar;36(3):1451-61. doi: 10.1016/j.neurobiolaging.2014.09.028. Epub 2014 Oct 2.
Diabetes and Alzheimer's disease share pathologic links toward cognitive deficits. Pharmacologic agonist of the nuclear receptor, peroxisomal proliferator-activating receptor gamma (PPARγ), that is, rosiglitazone (rosi), are insulin sensitizing agents that improve memory in Alzheimer's disease. However, direct molecular signaling targets that improve memory by PPARγ 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 brain-derived neurotrophic factor (BDNF) in db/db mice treated with rosi (ICV). Transcriptional activation of exon IX as determined by luciferase assays confirmed PPARγ regulation of BDNF promoter activity. Transient transfection of constitutively active PPARγ plasmid in hippocampal neuronal cells induced increased BDNF, AMPA, and NMDA receptors expression and spine formation. Findings from the present study implicate a novel PPARγ-BDNF molecular signaling mechanism as a potential therapeutic target for cognitive impairment.
糖尿病和阿尔茨海默病在导致认知缺陷方面存在病理联系。核受体过氧化物酶体增殖物激活受体γ（PPARγ）的药理激动剂，即罗格列酮（rosi），是能够改善阿尔茨海默病患者记忆力的胰岛素增敏剂。然而，PPARγ在海马体中改善记忆的直接分子信号靶点尚未得到研究。我们比较了2型糖尿病（db/db）小鼠经口服与脑室内（ICV）给予罗格列酮后在记忆及突触可塑性变化方面的结果。经罗格列酮（ICV）治疗的db/db小鼠在记忆、长时程增强和强直后增强方面有显著改善，但外周胰岛素敏感性未得到改善。基因和蛋白质分析显示，经罗格列酮（ICV）治疗的db/db小鼠脑源性神经营养因子（BDNF）增加。通过荧光素酶测定确定的外显子IX转录激活证实了PPARγ对BDNF启动子活性的调节。在海马神经元细胞中瞬时转染组成型活性PPARγ质粒可诱导BDNF、AMPA和NMDA受体表达增加以及树突棘形成。本研究结果表明一种新的PPARγ-BDNF分子信号机制是认知障碍的潜在治疗靶点。
