氢气与阿尔茨海默病中的嗅觉功能障碍：氢气-嗅觉-边缘系统假说

文献信息

中文摘要

背景： 嗅觉功能障碍日益被认为是阿尔茨海默病（AD）的早期临床特征，常先于可测量的认知损害出现，并与随后的认知下降相关。尽管这一临床关联相对一致，但AD中嗅觉功能障碍背后的解剖、细胞和生理学基础仍知之甚少。尸检人体研究已在嗅觉结构中鉴定出淀粉样蛋白-β（Aβ）和tau病理，包括嗅上皮和前嗅核。然而，现有解剖学证据仍然有限，且这些病理蛋白的存在并不能确立它们导致嗅觉功能障碍。同样，早期嗅觉损害究竟反映外周感觉功能障碍、神经元丢失、突触或环路异常、高级嗅觉处理改变、嗅觉-边缘网络破坏，还是这些过程的组合，仍不确定。尽管嗅上皮具有终身再生能力，但这种能力在AD进展过程中是否发生改变仍未解决。分子氢（H₂）在多种实验系统中已显示出抗氧化、抗炎、线粒体调节和细胞保护作用。然而，目前缺乏氢气改变AD相关嗅觉功能障碍的直接证据。在本观点文章中，我们提出氢气-嗅觉-边缘系统假说，作为一个可实验检验的框架，而非已确立的治疗机制。我们认为，分子氢可作为实验性干预手段，用以确定调节氧化、炎症和代谢过程是否影响AD进展过程中的嗅觉功能和嗅觉-边缘环路生理。该框架整合行为学、解剖学、分子、电生理、再生和连接性测量，以回答两个基本问题：AD中早期嗅觉功能障碍的原因是什么，以及分子氢能否改变与该表型相关的生物学相关过程？

英文摘要

Olfactory dysfunction is increasingly recognized as an early clinical feature of Alzheimer's disease (AD), often preceding measurable cognitive impairment and associated with subsequent cognitive decline. Despite this relatively consistent clinical association, the anatomical, cellular, and physiological substrates underlying olfactory dysfunction in AD remain poorly understood. Post-mortem human studies have identified amyloid-β (Aβ) and tau pathology in olfactory structures, including the olfactory epithelium and anterior olfactory nucleus. However, the available anatomical evidence remains limited, and the presence of these pathological proteins does not establish that they cause olfactory dysfunction. Likewise, it remains uncertain whether early olfactory impairment reflects peripheral sensory dysfunction, neuronal loss, synaptic or circuit abnormalities, altered higher-order olfactory processing, disruption of olfactory-limbic networks, or a combination of these processes. Although the olfactory epithelium possesses lifelong regenerative capacity, whether this capacity is altered during AD progression remains unresolved. Molecular hydrogen (H₂) has demonstrated antioxidant, anti-inflammatory, mitochondrial-modulatory, and cytoprotective effects in diverse experimental systems. However, direct evidence that hydrogen modifies AD-associated olfactory dysfunction is currently lacking. In this Perspective, we propose the Hydrogen-Olfactory-Limbic hypothesis as an experimentally testable framework rather than an established therapeutic mechanism. We suggest that molecular hydrogen can serve as an experimental intervention to determine whether modulating oxidative, inflammatory, and metabolic processes affects olfactory function and olfactory-limbic circuit physiology during AD progression. This framework integrates behavioral, anatomical, molecular, electrophysiological, regenerative, and connectivity measurements to address two fundamental questions: what causes early olfactory dysfunction in AD, and can molecular hydrogen modify biologically relevant processes associated with this phenotype?