Elucidating the role of Locus Coeruleus projections to the Cognitive Cerebellum in mouse models of Alzheimer's Disease (Administrative Supplement)

阐明蓝斑投射对阿尔茨海默氏病小鼠模型中认知小脑的作用（行政补充）

• 批准号: 10118991
• 负责人: Erik Sean Carlson
• 金额: $ 33.47万
• 依托单位: SEATTLE INST FOR BIOMEDICAL/CLINICAL RES
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10118991
• 关键词: Administrative Supplement; Affect; Age; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease model; Alzheimer' s disease patient; Alzheimer' s disease related dementia; Alzheimer' s disease risk; American; Applications Grants; Area; Behavior; Behavioral; Brain; Brain region; Cell Death; Cell Nucleus; Cerebellar Cortex; Cerebellum; Cessation of life; Clinical; Cognitive; Cognitive deficits; Data; Dementia; Deposition; Development; Disease; Dissection; Etiology; Fright; Frontotemporal Dementia; Funding; Future; Genetic; Grant; Hand; Human; Impaired cognition; Individual; Inflammation; Injections; Lateral; Lead; Learning; Low Prevalence; Mediating; Modeling; Morbidity - disease rate; Mus; Neurodegenerative Disorders; Neurofibrillary Tangles; Neurons; Onset of illness; Pathogenesis; Pathologic; Pathology; Pattern; Penetrance; Phenotype; Process; Progressive Supranuclear Palsy; Research Priority; Role; Short-Term Memory; Societies; Structure; Symptoms; Synapses; Tauopathies; Techniques; Testing; Transgenic Mice; Traumatic Brain Injury; United States National Institutes of Health; Viral; Virus; Work; abeta accumulation; advanced disease; age related; amyloid peptide; chronic traumatic encephalopathy; classical conditioning; cognitive function; early onset; experimental study; flexibility; innovation; insight; locus ceruleus structure; mortality; mouse model; nerve supply; neuron loss; neuropsychiatric disorder; neuropsychiatric symptom; noradrenergic; novel strategies; overexpression; response; symposium; tau Proteins; tau aggregation; tau-1

This supplemental grant proposal is for the currently funded RO1, “Genetic Dissection of Catecholaminergic Innervation of the Cognitive Cerebellum.” Work derived from this grant so far has implicated an noradrenergic projection circuit from the Locus Ceruleus (LC) to the dentate or lateral nucleus of the cerebellum (LCN) in mice as a locus modulating several cognitive behaviors affected by dementias such as Alzheimer's Disease, including working memory, response inhibition, associative learning of fear, and behavioral flexibility. We propose to interrogate the role of this circuit in order to understand tauopathies such as Alzheimer's Disease. Tauopathies are a group of progressive neurodegenerative disorders with no known disease modifying treatments. Tauopathies include a range of illnesses, including Alzheimer's disease (AD), Chronic Traumatic Encephalopathy (CTE) from traumatic brain injury, some frontotemporal dementias (FTD), and progressive supranuclear palsy (PSP). These illnesses are associated with cognitive dysfunction, neuropsychiatric symptoms, and collectively affect millions of Americans, causing significant morbidity and mortality. The cerebellum has different pathological patterns in these illnesses: in Alzheimer's disease, cerebellar tau deposition and cell death is seen in early onset and familial cases, whereas tau deposition and cell death in cerebellum is commonly seen in CTE, PSP and FTD. While a global effort to cure tauopathies is underway, it is estimated that merely suppressing or delaying the clinical expression of the particular tauopathy, AD, by half could lower the prevalence of dementia by ~80% because of its exponential relationship to age. The deposition of tau is a pathophysiological process that drives both synaptic and neuronal cell loss, leading to cognitive dysfunction. The essential neuropathologic changes of AD are the accumulation of β- amyloid (Aβ) peptides and hyperphosphorylated paired-helical filament (PHF)-τ containing neurofibrillary tangles. The distribution of Aβ and PHF-τ accumulation follows distinct stereotypic patterns across brain regions as AD advances and this pattern seems core to AD pathogenesis. It is also now clear that there is progressive degeneration and neuropathologic changes in subcortical regions of the AD brain. Aβ and PHF-τ deposition in the cerebellum is involved in AD cases with earlier disease onset and greater clinical penetrance. While LC degeneration has long been implicated in the pathogenesis of AD and LC is one of the first brain regions to develop PHF-τ containing neurofibrillary tangles, very little is known about the influence of PHF-τ in the LC on cognitive cerebellar function in AD or PSP. We hypothesize that tau pathology has direct and indirect effects on the cerebellum that contribute to cognitive impairment. We will interrogate the pathological and behavioral consequences with manipulations: first, we will characterize involvement of a LC->LCN circuit in a known mouse model of tauopathy, the P301L mouse line, and second, we will characterize the pathological and behavioral consequences of expressing hyperphosphorylated paired-helical filament (PHF)-τ in two regions: LC and LCN.

该补充拨款提案适用于目前资助的 RO1，“基因解剖” 迄今为止，这项资助的工作涉及认知小脑的儿茶酚胺神经支配。” 从蓝斑 (LC) 到齿状核或外侧核的去甲肾上腺素能投射回路 小鼠小脑（LCN）作为调节受痴呆症影响的多种认知行为的位点，例如 阿尔茨海默病，包括工作记忆、反应抑制、恐惧的联想学习，以及 我们建议探究该回路的作用，以了解诸如此类的tau蛋白病。 阿尔茨海默病是一组进行性神经退行性疾病，目前尚不清楚。 疾病修饰治疗包括一系列疾病，包括阿尔茨海默病 (AD)、 创伤性脑损伤引起的慢性创伤性脑病 (CTE)、某些额颞叶痴呆 (FTD)、 和进行性核上性麻痹（PSP）这些疾病与认知功能障碍有关， 神经精神症状，共同影响数百万美国人，导致严重的发病率和 小脑在这些疾病中具有不同的病理模式：在阿尔茨海默病中， 小脑 tau 沉积和细胞死亡见于早发型和家族性病例，而 tau 沉积和细胞死亡见于早发型和家族性病例，而 小脑细胞死亡常见于 CTE、PSP 和 FTD，而全球正在努力治愈 tau蛋白病。 正在进行中，估计只是抑制或延迟特定的临床表达 由于其指数关系，tau 蛋白病 (AD) 减半可将痴呆症患病率降低约 80% tau蛋白的沉积是一个导致突触和神经元细胞损失的病理生理过程， 导致认知功能障碍的AD的基本神经病理改变是β-的积累。 淀粉样蛋白 (Aβ) 肽和含有神经原纤维的过度磷酸化双螺旋丝 (PHF)-τ Aβ 和 PHF-τ 累积的分布遵循不同的大脑模式。 随着 AD 的进展，这种模式似乎是 AD 发病机制的核心。现在也清楚，存在这种现象。 AD 大脑皮层下区域的进行性退化和神经病理学变化。 小脑沉积与发病较早、临床外显率较高的 AD 病例有关。 虽然 LC 变性长期以来一直与 AD 的发病机制有关，并且 LC 是最早的大脑之一 区域发展出含有神经原纤维缠结的 PHF-τ，但人们对 PHF-τ 对神经原纤维缠结的影响知之甚少。 LC 对 AD 或 PSP 中认知小脑功能的影响 我们追求 tau 病理学具有直接和相关性。 对小脑的间接影响会导致认知障碍。 以及操作的行为后果：首先，我们将描述 LC->LCN 电路的参与情况 在已知的 tau 蛋白病小鼠模型（P301L 小鼠系）中，其次，我们将表征 表达过度磷酸化双螺旋丝 (PHF)-τ 的病理和行为后果 分为两个区域：LC 和 LCN。