Lietzau Grazyna, Nyström Thomas, Östenson Claes-Göran, Darsalia Vladimer, Patrone Cesare
Karolinska Institutet, Department of Clinical Science and Education, Södersjukhuset, Internal Medicine, Stockholm, Sweden.
Medical University of Gdansk, Department of Anatomy and Neurobiology, Gdansk, Poland.
Oncotarget. 2016 Feb 2;7(5):5865-76. doi: 10.18632/oncotarget.6823.
Type 2 diabetes (T2D) patients often present olfactory dysfunction. However, the histopathological basis behind this has not been previously shown. Since the piriform cortex plays a crucial role in olfaction, we hypothesize that pathological changes in this brain area can occur in T2D patients along aging. Thus, we determined potential neuropathology in the piriform cortex of T2D rats, along aging. Furthermore, we determined the potential therapeutic role of the glucagon-like peptide-1 receptor (GLP1-R) agonist exendin-4 to counteract the identified T2D-induced neuropathology. Young-adult and middle-aged T2D Goto-Kakizaki rats were compared to age-matched Wistars. Additional Goto-Kakizaki rats were treated for six weeks with exendin-4/vehicle before sacrifice. Potential T2D-induced neuropathology was assessed by quantifying NeuN-positive neurons and Calbindin-D28k-positive interneurons by immunohistochemistry and stereology methods. We also quantitatively measured Calbindin-D28k neuronal morphology and JNK phosphorylation-mediated cellular stress. PI3K/AKT signalling was assessed by immunohistochemistry, and potential apoptosis by TUNEL.We show T2D-induced neuronal pathology in the piriform cortex along aging, characterized by atypical nuclear NeuN staining and increased JNK phosphorylation, without apoptosis. We also demonstrate the specific vulnerability of Calbindin-D28k interneurons. Finally, chronic treatment with exendin-4 substantially reversed the identified neuronal pathology in correlation with decreased JNK and increased AKT phosphorylation.Our results reveal the histopathological basis to explain T2D olfactory dysfunction. We also show that the identified T2D-neuropathology can be counteracted by GLP-1R activation supporting recent research promoting the use of GLP-1R agonists against brain diseases. Whether the identified neuropathology could represent an early hallmark of cognitive decline in T2D remains to be determined.
2型糖尿病（T2D）患者常出现嗅觉功能障碍。然而，此前尚未揭示其背后的组织病理学基础。由于梨状皮质在嗅觉中起关键作用，我们推测该脑区的病理变化可能会随着衰老在T2D患者中出现。因此，我们确定了衰老过程中T2D大鼠梨状皮质中的潜在神经病理学变化。此外，我们还确定了胰高血糖素样肽-1受体（GLP1-R）激动剂艾塞那肽-4在对抗已确定的T2D诱导的神经病理学方面的潜在治疗作用。将年轻成年和中年T2D哥多-卡基萨基大鼠与年龄匹配的Wistar大鼠进行比较。另外的哥多-卡基萨基大鼠在处死前用艾塞那肽-4/载体治疗六周。通过免疫组织化学和体视学方法对NeuN阳性神经元和钙结合蛋白-D28k阳性中间神经元进行定量，以评估潜在的T2D诱导的神经病理学变化。我们还定量测量了钙结合蛋白-D28k神经元的形态以及JNK磷酸化介导的细胞应激。通过免疫组织化学评估PI3K/AKT信号通路，并通过TUNEL检测潜在的细胞凋亡。我们发现随着衰老，T2D会在梨状皮质中诱导神经元病理变化，其特征为NeuN染色核型异常和JNK磷酸化增加，但无细胞凋亡。我们还证明了钙结合蛋白-D28k中间神经元具有特定的易损性。最后，艾塞那肽-4的长期治疗与JNK降低和AKT磷酸化增加相关，显著逆转了已确定的神经元病理变化。我们的研究结果揭示了解释T2D嗅觉功能障碍的组织病理学基础。我们还表明，已确定的T2D神经病理学变化可通过GLP-1R激活得到对抗，这支持了最近关于促进使用GLP-1R激动剂治疗脑部疾病的研究。已确定的神经病理学变化是否可能代表T2D认知衰退的早期标志仍有待确定。
Zotero 插件
