Dissecting the mechanisms of Alzheimer's disease (AD)-related smell loss in a C. elegans AD model

项目摘要 作为一种致命的神经退行性疾病，阿尔茨海默病（AD）具有与年龄相关的进行性脑损伤 萎缩和神经元损失。在AD的所有病理标志物中，细胞内神经元缠结（NFT） 由过度磷酸化的tau蛋白和细胞外不溶性淀粉样蛋白斑块组成， 淀粉样（Aβ）肽的结构特征最好。然而，许多晚期临床试验针对 轻度至中度症状性AD患者的淀粉样蛋白或tau蛋白未能改变病程。一 潜在的原因是，即使在临床AD的中间阶段， 累积并发生不可逆的神经元损失。因此，应尽早采取干预措施， 尽可能地进入AD的临床前阶段。 最近，在正常认知期间嗅觉的快速下降已被证明可以预测随后的 老年人的认知障碍、痴呆和较小的灰质体积，表明嗅觉丧失 可能作为早期AD检测的简单生物标志物。然而，人们对细胞和 AD相关嗅觉丧失的分子机制（知识缺口）。最近，使用一个以前 建立C。elegans AD模型，我们发现这些AD蠕虫也表现出显着加速老化- 与年龄匹配的健康对照动物相比，依赖性嗅觉丧失，这表明我们可以使用这种方法， C. elegans AD模型研究AD相关嗅觉丧失的潜在机制。我们将首先研究 AD发病过程中化学感觉神经回路的脆弱性（目的1）。接下来，我们将调查 细胞和分子机制，化学感觉神经回路迅速失去其功能， AD发病机制（目的2）。 80%以上的C.线虫的基因在人类中有同源物。重要的是，许多AD相关基因具有 C.β-淀粉样蛋白前体蛋白（apl-1）、γ-分泌酶复合物（sel-12、hop-1 和spe-4）和微管相关蛋白MAP 2/MAP 4/MAPT/Tau（ptl-1）。作为C. elegans短 寿命，完全映射的神经回路，低维护成本和强大的遗传工具，我们希望我们的 建议使用C. elegans AD模型可以提供AD相关气味的机制见解 损失

Project Summary As a deadly neurodegenerative disorder, Alzheimer's disease (AD) features an age-related progressive brain atrophy and neuronal loss. Among all pathological markers of AD, intracellular neurofibrillary tangles (NFTs) composed of hyper-phosphorylated tau proteins and extracellular insoluble amyloid plaques mainly composed of amyloid (Aβ) peptide are the best characterized. However, numerous late stage clinical trials targeting amyloid or tau in patients with mild-to-moderate symptomatic AD have failed to modify the disease course. A potential reason is that even during the intermediate phase of clinical AD, enough pathology already accumulates and irreversible neuronal loss has occurred. Thus, interventions should be applied as early in the preclinical phase of AD as possible. Very recently, rapid smell decline during normal cognition period has been shown to predict subsequent cognitive impairment, dementia, and smaller gray matter volumes in older adults, indicating that smell loss might serve as a simple biomarker for early AD detection. However, little is known about the cellular and molecular mechanisms underlying the AD-related smell loss (knowledge gap). Recently, using a previously established C. elegans AD model, we found that these AD worms also exhibit significantly accelerated age- dependent smell loss compared to the age-matched healthy control animals, suggesting that we could use this C. elegans AD model to study the underlying mechanisms of AD-related smell loss. We will first study the vulnerability of chemosensory neural circuit during AD pathogenesis (Aim 1). Next, we will investigate the cellular and molecular mechanisms by which the chemosensory neural circuit rapidly loses its function upon AD pathogenesis (Aim 2). More than 80% of C. elegans genes have homologues in humans. Importantly, many AD-related genes have orthologues in C. elegans such as Amyloid Beta Precursor Protein (apl-1), γ-secretase complex (sel-12, hop-1 and spe-4), and microtubule associated protein MAP2/MAP4/MAPT/Tau (ptl-1). As C. elegans has short lifespan, fully mapped neural circuits, low maintenance cost, and powerful genetic tools, we expect that our proposed studies using the C. elegans AD model may provide mechanistic insights into the AD-related smell loss.