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

阿尔茨海默病大鼠模型中蓝斑激活的后果

• 批准号: 8711845
• 负责人: DAVID WEINSHENKER
• 金额: $ 174.71万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8711845
• 关键词: Acute; Alzheimer' s Disease; Alzheimer' s disease model; Amyloid beta-Protein Precursor; Amyloidosis; Animals; Apoptotic; Attenuated; Behavior; Brain; Brain Stem; Brain-Derived Neurotrophic Factor; Cell Count; Cell Nucleus; Cerebrum; Cessation of life; Chronic; Cognition; Cognitive; Cognitive deficits; Data; Dementia; Disease; Elderly; Faculty; Frequencies; Functional disorder; Goals; Healthcare Systems; Human; Impaired cognition; Injection of therapeutic agent; Intervention; Lasers; Lead; Learning; Lentivirus Vector; Lesion; Life; Light; Memory; Memory impairment; Mus; Nerve Degeneration; Neuroanatomy; Neurodegenerative Disorders; Neurofibrillary Tangles; Neuromodulator; Neurons; Neuropeptides; Norepinephrine; Outcome; Paper; Pathology; Patients; Peptides; Pharmaceutical Preparations; Physiologic pulse; Play; Process; Property; Prosencephalon; Psyche structure; Rattus; Relative (related person); Reliance; Research; Senile Plaques; Series; Signal Transduction; Societies; Source; Staging; Task Performances; Tauopathies; Therapeutic; Tissues; Transgenic Mice; Transgenic Organisms; Work; aged; base; cognitive function; design; improved; infancy; locus ceruleus structure; loved ones; mouse model; neurochemistry; neuroinflammation; neuron loss; neuropathology; neurotransmitter release; noradrenergic; optogenetics; prevent; promoter; public health relevance; research study; tau Proteins; tau aggregation; transmission process; treatment strategy

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.

描述(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，给社会带来巨大负担，其神经病理特征为淀粉样斑块和tau神经原纤维缠结。最近的一系列论文揭示了AD样的神经病理首先可以在蓝斑(LC)检测到，LC是一种脑干去甲肾上腺素能核，与学习和记忆有关，在AD早期退化。此外，在转基因小鼠的疾病模型中，LC损害加剧，而去甲肾上腺素能治疗改善AD样神经病理和认知障碍。然而，这些研究受到依赖于小鼠AD模型的限制，这些模型不能概括疾病的关键方面，如真正的tau缠结和神经元丢失。此外，目前的去甲肾上腺素能操作不能区分LC的两种不同的放电模式，即紧张性和相性，这两种模式对认知和神经递质释放有非常不同的影响。为了克服这些限制，我们将使用光遗传学来驱动TgF344-AD转基因大鼠的紧张性或相性LC活动，该转基因大鼠表现出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神经调节剂，负责LC的前认知和神经保护特性，从而为设计以LC为基础的治疗AD的方法奠定基础。

项目成果

Noradrenergic regulation of plasticity marker expression in the adult rodent piriform cortex.

• DOI: 10.1016/j.neulet.2017.02.060
• 发表时间: 2017-03-22
• 期刊: Neuroscience letters
• 影响因子: 2.5
• 作者: Vadodaria KC;Yanpallewar SU;Vadhvani M;Toshniwal D;Liles LC;Rommelfanger KS;Weinshenker D;Vaidya VA
• 通讯作者: Vaidya VA