Department of Anatomy and Medical Imaging and Centre for Brain Research, Faculty of Medical and Health Science, University of Auckland, Auckland 1023, New Zealand; Laboratory of Functional and Molecular Imaging, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.
Laboratory of Functional and Molecular Imaging, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.
Neuroscience. 2023 Apr 15;516:113-124. doi: 10.1016/j.neuroscience.2023.01.009. Epub 2023 Jan 28.
Years before Alzheimer's disease (AD) is diagnosed, patients experience an impaired sense of smell, and β-amyloid plaques accumulate within the olfactory mucosa and olfactory bulb (OB). The olfactory vector hypothesis proposes that external agents cause β-amyloid to aggregate and spread from the OB to connected downstream brain regions. To reproduce the slow accumulation of β-amyloid that occurs in human AD, we investigated the progressive accumulation of β-amyloid across the brain using a conditional mouse model that overexpresses a humanized mutant form of the amyloid precursor protein (hAPP) in olfactory sensory neurons. Using design-based stereology, we show the progressive accumulation of β-amyloid plaques within the OB and cortical olfactory regions with age. We also observe reduced OB volumes in these mice when hAPP expression begins prior-to but not post-weaning which we tracked using manganese-enhanced MRI. We therefore conclude that the reduced OB volume does not represent progressive degeneration but rather disrupted OB development. Overall, our data demonstrate that hAPP expression in the olfactory epithelium can lead to the accumulation and spread of β-amyloid through the olfactory system into the hippocampus, consistent with an olfactory system role in the early stages of β-amyloid-related AD progression.
早在阿尔茨海默病（AD）被诊断之前，患者就会出现嗅觉受损的情况，β-淀粉样蛋白斑块会在嗅黏膜和嗅球（OB）内积聚。嗅觉向量假说提出，外部因素会导致β-淀粉样蛋白聚集并从 OB 传播到连接的下游脑区。为了重现人类 AD 中β-淀粉样蛋白的缓慢积累，我们使用条件性小鼠模型研究了β-淀粉样蛋白在大脑中的渐进性积累，该模型在嗅觉感觉神经元中过度表达人源化突变形式的淀粉样前体蛋白（hAPP）。使用基于设计的立体学，我们显示了β-淀粉样蛋白斑块在 OB 和皮质嗅觉区域随年龄的逐渐积累。我们还观察到，在 hAPP 表达开始于断奶前而不是断奶后时，这些小鼠的 OB 体积减少，我们使用锰增强 MRI 来跟踪这一点。因此，我们得出结论，OB 体积的减少不是代表进行性退化，而是 OB 发育中断。总的来说，我们的数据表明，嗅上皮细胞中的 hAPP 表达可导致β-淀粉样蛋白通过嗅觉系统积累和传播到海马体，这与嗅觉系统在β-淀粉样蛋白相关 AD 进展的早期阶段的作用一致。
