Decoding Selective Vulnerability: Effectors and Regulators of Tau Lesion Spread in Alzheimer's Disease

摘要 阿尔茨海默氏病（AD）是痴呆症的最常见原因，也是美国人发病的主要原因。 国家，但仍然没有疾病修饰治疗的疾病机制是不完全的 明白AD的定义是脑中两种蛋白质病变的积累，淀粉样蛋白-β斑块和 神经系统缠结由聚集的tau蛋白组成的神经元缠结是一个更好的标志物 与淀粉样蛋白β相比，淀粉样蛋白β在疾病进展中的作用更大，与神经元丢失和认知能力下降相关。值得注意的是， 以Braak分期定义的刻板方式在大脑中扩散，从蓝斑开始， 沿着网络化的突触传播。这表明错误折叠的tau蛋白在突触中传播， 使正常tau蛋白模板也错误折叠并产生新的损伤。然而，有些地区从未 尽管平行突触暴露于蓝斑，但仍发生tau病变，表明选择性脆弱性 不同区域的tau病变。虽然一些AD病例是由于显性单基因突变， 绝大多数AD病例是散发的，没有明确的遗传原因。解决这种复杂性的一种方法是研究 基因表达对疾病的反应，以捕捉基因之间的功能相互作用。最 转录组学研究将其分析局限于大脑受影响区域的疾病反应， 将患病个体与正常对照进行比较。相比之下，我们的分析结合了选择性 特定脑区对发展中tau病变的脆弱性，比较脑的病变影响区域 在患病和对照个体中，将前额叶皮层（prefrontal cortex）转移到病变保护区（cerebellum）。根据 前提是两个区域都接受相同的顺行tau损伤，但差异表达是唯一的 保护小脑，这种比较将突出在从未发展的区域中神经保护的驱动因素 病变这种方法已经产生了一系列疾病神经保护的候选驱动因素，特别是丰富了 调节蛋白质折叠的伴侣蛋白。我们的分析还确定了几个转录因子（TF） 候选者，如核心时钟调节器BHLHE 40。这与对几种昼夜节律的观察一致。 在AD中观察到的表型，如睡眠障碍患者中AD的风险增加， 亦然该提案旨在通过几种方法测试我们的候选驱动基因。目标1将测试 鉴定了在诱导的生物化学模型中用于tau错误折叠的功能性抑制的伴侣蛋白。 重组tau蛋白固定化和体外用tau蛋白聚集的细胞生物传感器。目标2将测试TF候选人 用于在体外用tau聚集的细胞生物传感器调节tau聚集体积累。第三，目标 将在错误折叠的tau种子的小鼠模型中测试昼夜TF BHLHE 40如何调节tau扩散 注射这些目标将共同创造对AD tau蛋白病保护机制的新见解， 为疾病改善疗法的开发提供了多种新途径。

Abstract Alzheimer’s Disease (AD) is the most common cause of dementia and a major cause of morbidity in the United States, yet there remains no disease-modifying therapy as the mechanism of disease is incompletely understood. AD is defined by the accumulation of two protein lesions in the brain, amyloid-β plaques and neurofibrillary tangles. Neurofibrillary tangles, which are composed of aggregated tau protein, are a better marker of disease progression than amyloid-β, correlating with neuron loss and cognitive decline. Notably, tau tangles spread through the brain in a stereotypical fashion defined by Braak staging, starting in the locus coeruleus and spreading along networked synapses. This suggests that misfolded tau is propagated across the synapse, templating normal tau to become misfolded as well and generate new lesions. However, some regions never develop tau lesions despite parallel synaptic exposure to the locus coeruleus, suggesting selective vulnerability of different regions to tau lesions. Although some cases of AD are due to dominant single gene mutations, the vast majority of AD cases are sporadic with no clear genetic cause. One approach to such complexity is to study the gene expression response to disease in order to capture functional interactions between genes. Most transcriptomic studies have limited their analysis to the disease response in affected areas of the brain, comparing diseased individuals to normal controls. In contrast, our analysis incorporates the selective vulnerability of specific brain regions to developing tau lesions, comparing a lesion-affected area of the brain (prefrontal cortex) to a lesion-protected area (cerebellum) in both diseased and control individuals. According to the premise that both regions receive the same anterograde tau insult, but differential expression uniquely protects the cerebellum, this comparison will highlight the drivers of neuroprotection in areas that never develop lesions. This approach has yielded a list of candidate drivers of disease neuroprotection, notably enriching for chaperone proteins that regulate protein folding. Our analysis also identified several transcription factors (TF) candidates, such as the core clock regulator BHLHE40. This aligns with observations of several circadian phenotypes observed in AD, such as the increased risk of AD among patients with sleep disorders and vice versa. This proposal aims to test our candidate driver genes through several approaches. Aim 1 will test the identified chaperone proteins for functional inhibition of tau misfolding in both a biochemical model of induced recombinant tau fibrillization and in vitro with a cellular biosensor of tau aggregation. Aim 2 will test TF candidates for modulation of tau aggregate accumulation in vitro with a cellular biosensor of tau aggregation. Finally, Aim 3 will test how a circadian TF, BHLHE40, modulates tau spreading in a mouse model of misfolded tau seed injection. Together these aims will create new insight into mechanisms of protection from AD tauopathy and provide multiple new avenues for development of disease-modifying therapies.