Center for Neurodegenerative Science, Van Andel Research Institute, Grand Rapids, MI 49503, USA.
Department of Neurosciences, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA.
Neurobiol Dis. 2018 Jan;109(Pt B):226-248. doi: 10.1016/j.nbd.2016.12.013. Epub 2016 Dec 20.
Olfactory deficits are present in numerous neurodegenerative disorders and are accompanied by pathology in related brain regions. In several of these disorders, olfactory disturbances appear early and are considered as prodromal symptoms of the disease. In addition, pathological protein aggregates affect olfactory regions prior to other regions, suggesting that the olfactory system might be particularly vulnerable to neurodegenerative diseases. Exposed to the external environment, the olfactory epithelium and olfactory bulb allow pathogen and toxin penetration into the brain, a process that has been proposed to play a role in neurodegenerative diseases. Determining whether the olfactory bulb could be a starting point of pathology and of pathology spread is crucial to understanding how neurodegenerative diseases evolve. We argue that pathological changes following environmental insults contribute to the initiation of protein aggregation in the olfactory bulb, which then triggers the spread of the pathology within the brain by a templating mechanism in a prion-like manner. We review the evidence for the early involvement of olfactory structures in neurodegenerative diseases and the relationship between neuropathology and olfactory function. We discuss the vulnerability and putative underlying mechanisms by which pathology could be initiated in the olfactory bulb, from the entry of pathogens (promoted by increased permeability of the olfactory epithelium with aging or inflammation) to the sensitivity of the olfactory system to oxidative stress and inflammation. Finally, we review changes in protein expression and neural excitability triggered by pathogenic proteins that can promote pathogenesis in the olfactory bulb and beyond.
嗅觉缺陷存在于许多神经退行性疾病中，并伴有相关脑区的病理学改变。在这些疾病中，嗅觉障碍出现较早，被认为是疾病的前驱症状。此外，病理性蛋白聚集体在其他区域之前影响嗅觉区域，这表明嗅觉系统可能特别容易受到神经退行性疾病的影响。嗅觉上皮和嗅球暴露于外部环境中，允许病原体和毒素穿透大脑，这一过程被认为在神经退行性疾病中起作用。确定嗅球是否可以成为病理学的起点和病理学的传播点，对于理解神经退行性疾病的演变至关重要。我们认为，环境损伤后的病理变化导致嗅球中蛋白聚集的起始，然后通过类朊病毒模板机制引发病理学在大脑内的传播。我们回顾了嗅结构在神经退行性疾病中的早期参与以及神经病理学和嗅觉功能之间的关系。我们讨论了嗅球中病理学可能通过何种机制被引发的脆弱性和潜在机制，包括病原体的进入（由嗅上皮的通透性增加引起，随着年龄的增长或炎症而增加）、嗅觉系统对氧化应激和炎症的敏感性。最后，我们综述了致病蛋白引发的蛋白表达和神经兴奋性变化，这些变化可以促进嗅球及其他部位的发病机制。
