Olfactory dysfunction is an early and prevalent symptom of Alzheimer’s disease (AD) and the olfactory bulb is a nexus of beta-amyloid plaque and tau neurofibrillary tangle (NFT) pathology during early AD progression. To mitigate the accumulation of misfolded proteins, an endoplasmic reticulum stress response called the unfolded protein response (UPR) occurs in the AD hippocampus. However, chronic UPR activation can lead to apoptosis and the upregulation of beta-amyloid and tau production. Therefore, UPR activation in the olfactory system could be one of the first changes in AD. In this study, we investigated whether two proteins that signal UPR activation are expressed in the olfactory system of AD cases with low or high amounts of aggregate pathology. We used immunohistochemistry to label two markers of UPR activation (p-PERK and p-eIF2α) concomitantly with neuronal markers (NeuN and PGP9.5) and pathology markers (beta-amyloid and tau) in the olfactory bulb, piriform cortex, entorhinal cortex and the CA1 region of the hippocampus in AD and normal cases. We show that UPR activation, as indicated by p-PERK and p-eIF2α expression, is significantly increased throughout the olfactory system in AD cases with low (Braak stage III-IV) and high-level (Braak stage V-VI) pathology. We further show that UPR activation occurs in the mitral cells and in the anterior olfactory nucleus of the olfactory bulb where tau and amyloid pathology is abundant. However, UPR activation is not present in neurons when they contain NFTs and only rarely occurs in neurons containing diffuse tau aggregates. We conclude that UPR activation is prevalent in all regions of the olfactory system and support previous findings suggesting that UPR activation likely precedes NFT formation. Our data indicate that chronic UPR activation in the olfactory system might contribute to the olfactory dysfunction that occurs early in the pathogenesis of AD.

中文翻译：

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展开的蛋白质反应在阿尔茨海默氏病的嗅觉系统中被激活。

嗅觉功能障碍是阿尔茨海默氏病（AD）的早期和普遍症状，嗅球是AD早期发展过程中β-淀粉样斑块和tau神经原纤维缠结（NFT）病理的联系。为了减轻错误折叠的蛋白质的积累，在AD海马中发生了内质网应激反应，称为未折叠的蛋白质反应（UPR）。但是，慢性UPR激活会导致细胞凋亡以及β-淀粉样蛋白和tau产生的上调。因此，嗅觉系统中的UPR激活可能是AD的最初变化之一。在这项研究中，我们调查了两种表达UPR激活的蛋白是否在低或高聚集病理的AD病例的嗅觉系统中表达。我们使用免疫组织化学标记了UPR激活的两个标记（p-PERK和p-eIF2α）以及嗅球，梨状皮层，内嗅皮层中的神经元标记（NeuN和PGP9.5）和病理标记（β-淀粉样蛋白和tau）。 AD和正常人的海马CA1区。我们显示，如p-PERK和p-eIF2α表达所示，UPR激活在低（Braak III-IV期）和高水平（Braak V-VI期）病理性AD患者的整个嗅觉系统中均显着增加。我们进一步表明，UPR激活发生在二头细胞和tau和淀粉样蛋白病理丰富的嗅球的前嗅核中。但是，当包含NFT的神经元中不存在UPR激活，而在包含弥散tau聚集体的神经元中很少发生。我们得出的结论是，UPR激活在嗅觉系统的所有区域中都很普遍，并支持以前的发现，表明UPR激活可能先于NFT形成。我们的数据表明，嗅觉系统中的慢性UPR激活可能是AD发病早期发生的嗅觉功能障碍的原因。