Local and global consequences of hyperphosphorylated tau in the locus coeruleus in Alzheimer's Disease

项目总结 阿尔茨海默病(AD)是世界范围内最常见的痴呆症，困扰着近4600万人 人民。AD的两种标志性病理是细胞外β-淀粉样蛋白(Aβ)斑块和细胞内聚集 Tau，称为神经原纤维缠结。许多针对疾病中晚期淀粉样蛋白沉积的治疗方法 在动物模型中有效，但在临床试验中失败。然而，最近的证据表明， 去甲肾上腺素能蓝斑(LC)中过度磷酸化的“前缠结”tau出现在几十年前 认知症状和Aβ沉积，为AD的潜在原因和进展提供了新的见解。这个 LC通过在靶部位释放去甲肾上腺素来协调不同的大脑状态，并且许多LC调节 AD患者的行为会出错，但很少有研究直接调查tau异常对LC的影响 功能。Tau的异常表达导致神经元活动不足，tau负荷与迟钝的新颖性有关。 反应，这是受LC活动影响的关键行为。此外，LC没有表现出坦率的神经元丢失。 直到疾病晚期，认知能力明显下降，但神经元形态改变，神经支配 在疾病的早期阶段，密度会降低。尽管有这些潜在的致病变化，我们的数据表明 LC的激活有可能恢复正常认知。在TgF344-AD转基因大鼠中，类似于 人类，过度磷酸化的tau出现在LC中，先于tau或前脑的Aβ病理。重要的是 化学激活LC可有效修复老年TgF344-AD大鼠的空间学习障碍。 这表明，即使在LC和AD样神经病变存在的情况下，LC刺激也能增强认知能力 前脑。然而，目前还没有关于tau对LC生理或LC诱导的改变的影响的信息 在全脑的功能连接中。 在这个拟议的项目中，我将使用TgF344-AD大鼠来评估tau介导的LC神经元功能障碍 以及LC刺激纠正功能连接体退化的治疗潜力。在目标1中，我将使用 体内电生理学以确定LC中过度磷酸化的tau是否可以改变神经元的放电频率 以年龄相关的方式。在目标2中，我将结合LC的光遗传刺激和同步 功能磁共振成像评估LC刺激能否挽救全脑网络 功能性连接缺陷。我假设tau的异常会降低神经元的放电率- 依赖的方式将伴随着渐进的全脑连接不足，这将通过以下方式得到纠正 光遗传LC刺激。这些目标的完成将决定最早的 已知的AD病理，LC中过度磷酸化的tau，并促进LC-NE治疗的发展 延缓病情进展的干预措施。

PROJECT SUMMARY Alzheimer’s disease (AD) is the most common form of dementia world-wide, afflicting nearly 46 million people. The two hallmark AD pathologies are extracellular β-amyloid (Aβ) plaques and intracellular aggregated tau, termed neurofibrillary tangles. Many treatments that target amyloid deposition in mid to late stages of disease are effective in animal models but have failed in clinical trials. However, recent evidence indicates that hyperphosphorylated “pre-tangle” tau in the noradrenergic locus coeruleus (LC) appears decades prior to cognitive symptoms and Aβ deposition, offering fresh insight into the potential cause and progression of AD. The LC coordinates distinct brain states through norepinephrine release at target sites, and many LC-modulated behaviors go awry in AD, but few studies have directly investigated the consequences of aberrant tau on LC function. Aberrant tau expression causes hypoactivity in neurons, and tau load is associated with blunted novelty response, a key behavior influenced by LC activity. Furthermore, the LC does not exhibit frank neuronal loss until late stages of disease when cognitive decline is evident, but neuron morphology is altered, and innervation density is decreased at early stages of disease. Despite these potentially pathogenic changes, our data indicates that activation of the LC has the potential to restore normal cognition. In TgF344-AD transgenic rats, similar to humans, hyperphosphorylated tau appears in the LC prior to tau or Aβ pathology in the forebrain. Importantly, chemogenetic activation of the LC is effective at rescuing spatial learning deficits in aged TgF344-AD rats, indicating that LC stimulation enhances cognition even in the presence of AD-like neuropathology in the LC and forebrain. However, there is no information regarding the effects of tau on LC physiology or LC-induced changes in brain-wide functional connectivity. In this proposed project, I will use TgF344-AD rats to assess both tau-mediated LC neuron dysfunction and the therapeutic potential of LC stimulation to correct functional connectome deterioration. In Aim 1, I will use in vivo electrophysiology to determine whether hyperphosphorylated tau in the LC can alter neuron firing rates in an age-dependent manner. In Aim 2, I will combine optogenetic stimulation of the LC with simultaneous functional magnetic resonance imaging to assess whether LC stimulation can rescue brain-wide network functional connectivity deficits. I hypothesize that aberrant tau will decrease neuron firing rates in an age- dependent manner that will be paralleled by gradual, brain-wide hypoconnectivity, which will be corrected by optogenetic LC stimulation. Completion of these aims will determine the functional consequences of the earliest known AD pathology, hyperphosphorylated tau in the LC, and facilitate development of LC-NE based therapeutic interventions to retard progression.