Durand Daniela, Carniglia Lila, Beauquis Juan, Caruso Carla, Saravia Flavia, Lasaga Mercedes
Instituto de Investigaciones Biomédicas (INBIOMED), School of Medicine, University of Buenos Aires - CONICET, Paraguay 2155, Ciudad Autónoma de Buenos Aires 1121, Argentina.
Laboratorio de Neurobiología, Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Intendente Güiraldes 2160, Ciudad Autónoma de Buenos Aires 1428, Argentina; Instituto de Biología y Medicina Experimental, CONICET, Vuelta de Obligado 2490, Ciudad Autónoma de Buenos Aires 1428, Argentina.
Neuropharmacology. 2014 Apr;79:180-9. doi: 10.1016/j.neuropharm.2013.11.015. Epub 2013 Dec 1.
Amyloid precursor protein (APP) shedding yields the Alzheimer's disease (AD)-related peptide amyloid β (Aβ) through β- and γ-secretase cleavage. Alternatively, α-secretase cleavage generates a soluble and neuroprotective fragment (sAPPα) while precludes the production of Aβ. Although metabotropic glutamate (mGlu) receptors were associated with induction of sAPPα production in astrocytes, there was no further evidence regarding the specific subtype receptor or the mechanisms involved in this action. In the present study, we used the dual mGlu2/3 receptor agonist LY379268, which in pure astrocyte cultures selectively activates mGlu3 receptor subtype since mGlu2 receptor subtype is not expressed by these cells. We showed that LY379268 incremented sAPPα release from cultured astrocytes by inducing α-secretases expression, whereas it decreased β-secretase levels. LY379268-induced increase of PPAR-γ levels could be involved in the effect of the agonist on sAPPα release. Using the PDAPP-J20 murine model of AD we described a strong reduction in mGlu2/3 receptor expression in the hippocampus of 5- and 14-month-old transgenic mice compared to control littermates. Moreover, mGlu3 receptor expression is also decreased specifically in hippocampal astrocytes of these transgenic animals as a function of age. Therefore, diminished levels of hippocampal mGlu3 receptors might have implications in the development of the disease in these transgenic mice considering the anti-amyloidogenic action of mGlu3 receptors in astrocytes.
淀粉样前体蛋白（APP）经蛋白水解产生与阿尔茨海默病（AD）相关的肽类淀粉样β蛋白（Aβ），这一过程通过β-和γ-分泌酶的切割作用实现。另外，α-分泌酶的切割作用可产生一种可溶性的具有神经保护作用的片段（sAPPα），同时可防止Aβ的产生。尽管代谢型谷氨酸（mGlu）受体与星形胶质细胞中sAPPα生成的诱导有关，但关于具体的亚型受体或此作用涉及的机制尚无进一步证据。在本研究中，我们使用了双mGlu2/3受体激动剂LY379268，在纯星形胶质细胞培养物中，由于这些细胞不表达mGlu2受体亚型，所以该激动剂可选择性激活mGlu3受体亚型。我们发现，LY379268通过诱导α-分泌酶的表达增加了培养的星形胶质细胞中sAPPα的释放，而降低了β-分泌酶的水平。LY379268诱导的过氧化物酶体增殖物激活受体γ（PPAR-γ）水平的升高可能与该激动剂对sAPPα释放的作用有关。利用AD的PDAPP-J20小鼠模型，我们发现与同窝对照小鼠相比，5月龄和14月龄转基因小鼠海马中mGlu2/3受体的表达显著降低。此外，随着年龄的增长，这些转基因动物海马星形胶质细胞中mGlu3受体的表达也特异性降低。因此，考虑到mGlu3受体在星形胶质细胞中的抗淀粉样变性作用，海马mGlu3受体水平的降低可能对这些转基因小鼠疾病的发展有影响。
