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.

该补充赠款提案是针对当前资助的RO1的“遗传解剖的 认知小脑的儿茶酚胺能神经。 从ceruleus（LC）到齿状或外侧核的去甲肾上腺素能投影电路 小鼠的小脑（LCN）作为一个基因座调节受痴呆症影响的几种认知行为，例如 阿尔茨海默氏病，包括工作记忆，反应抑制，恐惧的联想学习和 行为灵活性。我们建议询问该电路的作用 作为阿尔茨海默氏病。陶氏病是一组进行性神经退行性疾病，尚无已知的疾病 疾病修改治疗。陶氏病包括一系列疾病，包括阿尔茨海默氏病（AD）， 脑外伤性脑病（CTE）因创伤性脑损伤，一些额颞痴呆（FTD）， 和进行性上腹部麻痹（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，引起了明显的发病率和 死亡。小脑在这些疾病中具有不同的病理模式：在阿尔茨海默氏病， 小脑tau沉积和细胞死亡在早期和家族病例中可见，而tau的沉积和 小脑中的细胞死亡通常在CTE，PSP和FTD中可见。虽然全球治愈tauopathies的努力是 正在进行中，据估计，仅抑制或延迟特定的临床表达 Tauopathy，AD，由于其指数关系，痴呆症的患病率可能会降低约80％ 年龄。 TAU的沉积是一个病理生理过程，驱动合成和神经元细胞损失， 导致认知功能障碍。 AD的基本神经病理学变化是β-的积累 淀粉样蛋白（Aβ）肽和磷酸化的成对螺丝丝（PHF） - 含有神经纤维 缠结。 Aβ和PHF-τ积累的分布遵循跨大脑的不同刻板印象模式 随着AD的进步和这种模式，区域似乎是AD发病机理的核心。现在也很明显有 AD大脑皮层下区域的进行性变性和神经病理学变化。 Aβ和PHF-τ 小脑中的沉积与早期疾病发作和更大临床渗透率的AD病例有关。 虽然LC变性长期以来在AD和LC的发病机理中隐含是第一个大脑之一 开发含有神经原纤维缠结的PHF-τ的区域，对PHF-τ的影响知之甚少 AD或PSP认知小脑功能的LC。我们假设Tau病理学有直接和 对小脑的间接影响会导致认知障碍。我们将审问病理 和操纵的行为后果：首先，我们将表征LC-> LCN电路的参与 在已知的tauopathy的鼠标模型中，P301L鼠标线，其次，我们将表征 表达高磷酸化的成对螺丝丝（PHF）-τ的病理和行为后果 在两个区域：LC和LCN。