Consequences of Locus Coeruleus Activation in a Rat Model of Alzheimer's Disease

描述（由申请人提供）：阿尔茨海默病（AD）是一种神经退行性疾病，是老年人痴呆症最常见的原因，给社会带来了巨大的负担，其神经病理学特征是-淀粉样斑块和tau神经原纤维缠结。最近的一系列论文表明，AD样神经病理可以首先在蓝斑核（LC）中检测到，蓝斑核是一种脑干去肾上腺素能核，与学习和记忆有关，在AD早期退化。此外，LC病变加剧，而去甲肾上腺素能治疗可改善ad样神经病理和认知缺陷的转基因小鼠模型。然而，这些研究受到依赖小鼠AD模型的限制，这些模型不能概括该疾病的关键方面，如真正的tau缠结和神经元丢失。此外，目前的去肾上腺素能操作无法区分LC放电的两种不同模式，强直和相位，这两种模式对认知和神经递质释放的影响非常不同。为了克服这些限制，我们将利用光遗传学来驱动TgF344-AD转基因大鼠的强直性或阶段性LC活性，这些大鼠表现出AD的所有关键神经病理和认知特征。这些研究的完成将确定最有益的放电模式和负责LC的促认知和神经保护特性的神经调节剂，从而为设计基于LC的治疗AD的疗法奠定基础。

DESCRIPTION (provided by applicant): Alzheimer's disease (AD), a neurodegenerative disease that is the most common cause of dementia in the elderly and poses immense burdens on society, is characterized neuropathologically by ¿-amyloid plaques and tau neurofibrillary tangles. A recent series of papers has revealed that AD-like neuropathology can first be detected in the locus coeruleus (LC), a brainstem noradrenergic nucleus implicated in learning and memory that degenerates early in AD. Furthermore, LC lesions exacerbate, while pro-noradrenergic treatments ameliorate, AD-like neuropathology and cognitive deficits in transgenic mouse models of the disease. However, these studies have been limited by reliance on mouse AD models that do not recapitulate critical aspects of the disease such as bona fide tau tangles and neuronal loss. In addition, current noradrenergic manipulations cannot distinguish between the two distinct modes of LC firing, tonic and phasic, which have very different effects on cognition and neurotransmitter release. To overcome these limitations, we will use optogenetics to drive tonic or phasic LC activity in the TgF344-AD transgenic rat that manifests all critical neuropathological and cognitive hallmarks of AD. Completion of these studies will identify the most beneficial firing modes and neuromodulators responsible for the pro-cognitive and neuroprotective properties of the LC, thus laying the groundwork for the design of LC-based therapies for the treatment of AD.