Department of Brain & Cognitive Sciences, Graduate School, Daegu Gyeungbuk Institute of Science and Technology (DGIST), Daegu, Republic of Korea.
School for Mental Health and Neuroscience, Maastricht University, Maastricht, the Netherlands.
Alzheimers Res Ther. 2021 Jan 4;13(1):4. doi: 10.1186/s13195-020-00730-2.
Hyposmia in Alzheimer's disease (AD) is a typical early symptom according to numerous previous clinical studies. Although amyloid-β (Aβ), which is one of the toxic factors upregulated early in AD, has been identified in many studies, even in the peripheral areas of the olfactory system, the pathology involving olfactory sensory neurons (OSNs) remains poorly understood.
Here, we focused on peripheral olfactory sensory neurons (OSNs) and delved deeper into the direct relationship between pathophysiological and behavioral results using odorants. We also confirmed histologically the pathological changes in 3-month-old 5xFAD mouse models, which recapitulates AD pathology. We introduced a numeric scale histologically to compare physiological phenomenon and local tissue lesions regardless of the anatomical plane.
We observed the odorant group that the 5xFAD mice showed reduced responses to odorants. These also did not physiologically activate OSNs that propagate their axons to the ventral olfactory bulb. Interestingly, the amount of accumulated amyloid-β (Aβ) was high in the OSNs located in the olfactory epithelial ectoturbinate and the ventral olfactory bulb glomeruli. We also observed irreversible damage to the ectoturbinate of the olfactory epithelium by measuring the impaired neuronal turnover ratio from the basal cells to the matured OSNs.
Our results showed that partial and asymmetrical accumulation of Aβ coincided with physiologically and structurally damaged areas in the peripheral olfactory system, which evoked hyporeactivity to some odorants. Taken together, partial olfactory dysfunction closely associated with peripheral OSN's loss could be a leading cause of AD-related hyposmia, a characteristic of early AD.
根据许多先前的临床研究，阿尔茨海默病（AD）患者的嗅觉减退是一种典型的早期症状。尽管淀粉样蛋白-β（Aβ）被认为是 AD 早期上调的毒性因素之一，但在许多研究中，甚至在外周嗅觉系统区域都发现了 Aβ，而涉及嗅觉感觉神经元（OSN）的病理学仍知之甚少。
在这里，我们专注于外周嗅觉感觉神经元（OSN），并使用气味剂更深入地研究了病理生理学和行为结果之间的直接关系。我们还通过组织学确认了 3 月龄 5xFAD 小鼠模型中的病理变化，该模型再现了 AD 病理学。我们引入了一个数值量表来组织学比较生理现象和局部组织损伤，而不考虑解剖平面。
我们观察到 5xFAD 小鼠对气味剂的反应减少，而气味剂组的 OSN 没有生理激活。有趣的是，位于嗅上皮外鼻甲和嗅球肾小球的 OSN 中积累的淀粉样蛋白-β（Aβ）量很高。通过测量从基底细胞到成熟 OSN 的受损神经元更替率，我们还观察到嗅上皮外鼻甲不可逆的损伤。
我们的结果表明，Aβ 的部分和不对称积累与外周嗅觉系统的生理和结构损伤区域相吻合，这导致对某些气味剂的反应减弱。综上所述，与外周 OSN 丧失相关的部分嗅觉功能障碍可能是 AD 相关嗅觉减退的主要原因，这是 AD 的一个特征。
