Yao Zhi-Gang, Jing Hai-Yan, Wang Dong-Mei, Lv Bei-Bei, Li Jia-Mei, Liu Feng-Feng, Fan Hui, Sun Xi-Chao, Qin Ye-Jun, Zhao Miao-Qing
Department of Pathology, Shandong Provincial Hospital Affiliated to Shandong University, No. 324 Jingwu Road, Jinan 250021, China.
Department of Pathogen Biology, Medical College, Henan University of Science and Technology, Building 6, Anhui Jianxi District, Luoyang 471003, China.
Pharmacol Biochem Behav. 2016 May;144:53-9. doi: 10.1016/j.pbb.2016.02.012. Epub 2016 Mar 3.
Olfactory dysfunction is a common and early symptom of many neurodegenerative diseases, particularly of Alzheimer's disease (AD) and mild cognitive impairment, pointing to the progression to dementia. Recent studies have revealed that valproic acid (VPA) has neuroprotective effects in rodent models of AD. In this study, we investigated the effects of VPA on olfactory dysfunction of APP/PS1 double transgenic mouse models of AD. After continuous treatment with a 100mg/kg daily dose of VPA for 3 months, APP/PS1 mice showed improved olfactory performances. In agreement with the behavioral findings, VPA treatment reduced amyloid β (Aβ) burden in the olfactory epithelium (OE) of transgenic mice. And, VPA increased epithelial thickness of the olfactory mucosa through decreased cell apoptosis and increased cell proliferation. In the olfactory bulb (OB), VPA administration also reduced senile plaques and levels of soluble and insoluble Aβ42 peptides. Besides, VPA promoted the increase of mitral cells and decrease of neurofilament immunostaining. In hence, VPA treatment completely improved the olfactory performances and prevented degenerative changes of the OE and OB. Our study raises the possibility of AD diagnosis by OE biopsy. Moreover, VPA may provide a novel therapeutic strategy for the treatment of olfactory dysfunction in AD patients.
嗅觉功能障碍是许多神经退行性疾病常见的早期症状，尤其是阿尔茨海默病（AD）和轻度认知障碍，预示着病情会发展为痴呆。最近的研究表明，丙戊酸（VPA）在AD的啮齿动物模型中具有神经保护作用。在本研究中，我们调查了VPA对AD的APP/PS1双转基因小鼠模型嗅觉功能障碍的影响。以每日100mg/kg的剂量连续给APP/PS1小鼠治疗3个月后，其嗅觉表现有所改善。与行为学结果一致，VPA治疗降低了转基因小鼠嗅上皮（OE）中的淀粉样β蛋白（Aβ）负荷。并且，VPA通过减少细胞凋亡和增加细胞增殖，增加了嗅黏膜的上皮厚度。在嗅球（OB）中，给予VPA也减少了老年斑以及可溶性和不溶性Aβ42肽的水平。此外，VPA促进了二尖瓣细胞的增加和神经丝免疫染色的减少。因此，VPA治疗完全改善了嗅觉表现，并防止了OE和OB的退行性变化。我们的研究提出了通过OE活检诊断AD的可能性。此外，VPA可能为治疗AD患者的嗅觉功能障碍提供一种新的治疗策略。
