Impact of locus coeruleus-derived tau pathology in a rodent model of early Alzheimer's disease

淀粉样蛋白-β(A-β)斑块和tau神经原纤维缠结以及神经元死亡是病理特征 阿尔茨海默病(AD)。到目前为止，针对Aβ的治疗努力都失败了，这突显了 需要其他方法，特别是那些可以针对早期AD的方法。蓝斑中异常的tau蛋白 (LC)，大脑中主要的去甲肾上腺素能核，调节注意力、觉醒、应激反应和 认知，是人类大脑中最早可检测到的AD样神经病理，而LC变性是 在公元后期无处不在。最近的研究表明，早期LC功能障碍可能与先兆AD有关 抑郁、焦虑和睡眠障碍等症状，而后来的LC变性会加剧认知 减损。尽管这些数据表明LC是治疗AD的一个有前途的治疗靶点，但几乎没有 了解致病tau如何影响LC功能和生存。我们已经开发出一种病毒载体， 驱动野生型人tau蛋白在LC神经元中的特异表达，随着时间的推移，它会变成 过度磷酸化和错误折叠，从而概括了人类AD的最早形式。我们将用这本小说 在LC中研究tau病理后果的工具。在目标1中，我们将确定不同 异常tau的形式对LC神经元的形态、存活和局部炎症的影响，并评估其潜在的 LC衍生的tau病理扩散到相互连接的前脑区域。在目标2中，我们将在体内使用 评估tau病理如何影响LC活动和表现的电生理学和行为范式 在神经精神和认知领域。在目标3中，我们将结合光遗传学和功能磁共振成像来确定 Tau蛋白的异常影响LC-前脑的功能连接。这些目标的实现将奠定基础 用于早期AD的LC/tau治疗。

Amyloid-β (Aβ) plaques and tau neurofibrillary tangles, as well as neuronal death, are the pathologic hallmarks of Alzheimer's disease (AD). Therapeutic efforts focused on Aβ have thus far failed, underscoring the urgent need for alternate approaches, particularly those that can target early AD. Aberrant tau in the locus coeruleus (LC), the major noradrenergic nucleus in the brain that regulates attention, arousal, stress responses, and cognition, is the earliest detectable AD-like neuropathology in the human brain, and LC degeneration is ubiquitious in later AD. Recent research indicates that early LC dysfunction may contribute to prodromal AD symptoms such as depression, anxiety, and sleep disorders, while later LC degeneration exacerbates cognitive impairment. Although these data suggest that the LC is a promising therapeutic target in AD, almost nothing known about how pathogenic tau impacts LC function and survival. We have developed a viral vector that drives the expression of wild-type human tau exclusively in LC neurons, which over time becomes hyperphosphorylated and misfolded, thus recapitulating the earliest forms of human AD. We will use this novel tool to study the consequences tau pathology in the LC. In Aim 1, we will determine the impact of different forms of aberrant tau on LC neuron morphology, survival, and local inflammation, and assess the potential of LC-derived tau pathology to spread to interconnected forebrain regions. In Aim 2, we will use in vivo electrophysiology and behavioral paradigms to evaluate how tau pathology affects LC activity and performance in neuropsychiatric and cognitive domains. In Aim 3, we will combine optogenetics and fMRI to determine how aberrant tau influences LC-forebrain functional connectivity. Completion of these aims will lay the groundwork for LC/tau-based therapies for early AD.