Consequences of Noradrenergic Degeneration in the Novel TgF344-AD Rat Model

新型 TgF344-AD 大鼠模型中去甲肾上腺素能变性的后果

基本信息

批准号：
10581841
负责人：
LORI Lynn MCMAHON
金额：
$ 58.8万
依托单位：
MEDICAL UNIVERSITY OF SOUTH CAROLINA
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-15 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10581841
关键词：
AD transgenic mice APP-PS1 Adrenergic Agents Adrenergic Receptor Aging Agitation Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease patient Amyloid beta-Protein Anxiety Attention Axon Back Behavior Biochemistry Biology Brain Brain region Cells Chemicals Chemosensitization Clinical Cognition Cognitive Cognitive deficits Control Locus Data Denervation Disease Disease Progression Distal Electrophysiology (science)Estradiol Female Fiber Fright Functional disorder Hippocampal Formation Hippocampus (Brain)Human Impairment Intervention Learning Lesion Light Link Literature Mainstreaming Masks Medial Memory Menopause Mental Health Modeling Mus Neurons Norepinephrine Outcome Ovarian hormone Pathologic Pathology Patients Perforant Pathway Pharmacology Phosphorylation Plasma Positioning Attribute Post-Translational Protein Processing Proestrus Prosencephalon Rattus Reporting Research Role Serine Sex Differences Slice Source Synapses Synaptic Transmission System Testing Therapeutic Therapeutic Intervention Threonine Transgenic Organisms Up-Regulation Woman Work abeta accumulation axonal degeneration basal forebrain beta-2 Adrenergic Receptors beta-adrenergic receptor cholinergic comorbid depression comorbidity density dentate gyrus emerging adult experience granule cell health knowledge human disease hyperphosphorylated tau improved innovation locus ceruleus structure male mouse model neglect nerve supply neuroinflammation neuronal excitability noradrenergic novel pre-clinical preservation prevent prodromal Alzheimer&apos s disease receptor function sex sexual dimorphism spatial memory synaptic function tau aggregation tau-1

项目摘要

Project Summary Noradrenergic (NA) input to hippocampus from locus coeruleus (LC), the sole supplier of NA innervation to forebrain, is required for acquisition and consolidation of spatial learning and memory and contextual fear behavior. The dentate gyrus (DG) contains the highest NA content, greatest NA fiber density, and largest expression of β1-and β2-adrenergic receptors (ARs) in the hippocampal formation, consistent with DG being a key region of modulatory control by LC. There is a rich literature dating back to the mid 1980’s showing a critical role for β-ARs in facilitating induction of both LTP and LTD at DG synapses depending upon the saliency of the experience. This heightened plasticity occurs simultaneous with heightened learning and memory, and both are prevented by loss of NA innervation or pharmacological blockade of β-ARs. Importantly, the LC in females has a larger volume, LC neurons have greater dendritic arbors, and at proestrus, when plasma estradiol levels are the highest, NA neuronal activity is decreased. The LC is the first brain region damaged in Alzheimer’s disease (AD), due to accumulation of hyper- phosphorylated tau (p-tau). The consequence of this pathology is greatly under-appreciated since transgenic AD mouse models do not recapitulate this feature of human disease. Fortunately, the novel TgF344-AD rat model has significant p-tau accumulation in LC and NA axon loss in hippocampus, permitting detailed studies of LC and NA system dysfunction on hippocampal synaptic transmission and learning and memory. Clearly, identifying strategies to prevent p-tau accumulation and LC damage is critical. The post-translational modification, O- GlcNAcylation, has been shown to do just this through competition with phosphorylation at key serine residues on p-tau that cause its accumulation. Using brain slice electrophysiology, we reported pathologically heightened LTP at medial perforant path synapses in dentate gyrus prior to CA1 synapses in both sexes. In recent data, we find heightened potentiation at medial perforant path synapses following pharmacological activation of β-ARs. This upregulation of β-AR function in the context NA fiber loss likely drives the heightened LTP and masks deficits in learning and memory early in the disease. The current proposal will test the hypothesis that hippocampal noradrenergic function in AD is impaired via aberrant excitability of LC-NA cells caused by progressive p-tau accumulation and through NA denervation, both of which will be worse in ovariectomized females and protected by O-GlcNAcylation. We will use a combination of electrophysiology in hippocampus and locus coeruleus, hippocampus-dependent behavior, pharmacology, biochemistry, and O-GlcNAc biology to test this innovative hypothesis. Outcomes will shed new light on the role of LC damage in AD, and will lay the ground work for therapeutic strategies targeting the LC and perhaps O-GlcNAcylation.

项目摘要 NA神经支配的唯一供应商前脑是获得和巩固空间学习和记忆以及上下文恐惧所必需的行为。齿状回（DG）包含最高的Na含量，最大的Na纤维密度和最大的海马形成中β1和β2-肾上腺素能受体（ARS）的表达，与DG为A LC的调节控制的关键区域。有一本丰富的文献可以追溯到1980年代中期，显示了关键 β-AR在DG突触中支持LTP和LTD诱导LTP和LTD的作用，取决于显着性经验。这种增强的可塑性同时发生了学习和记忆的增强，两者都是通过失去NA神经或药物阻断β-AR的阻止。重要的是，女性的LC有较大的LC神经元具有更大的树突状乔木，而在血浆雌二醇水平为最高的NA神经元活性降低。 LC是阿尔茨海默氏病（AD）中第一个脑部区域，由于高度积累磷酸化的tau（p-tau）。由于转基因广告，这种病理的结果被低估了小鼠模型不会概括人类疾病的这一特征。幸运的是，新型TGF344-AD大鼠模型在海马中，LC和Na轴突损失有明显的P-TAU积累，允许对LC进行详细研究和NA系统功能障碍在海马合成传播，学习和记忆方面。显然，识别防止P-TAU积累和LC损伤的策略至关重要。翻译后修改，o- Glcnacylation已被证明通过在关键串行保留下与磷酸化的竞争来做到这一点在p-tau上导致其积累。据报道，使用大脑切片电生理学，我们提高了在两性中，在Ca1突触之前，在齿状回的内侧穿孔路径突触中的LTP。在最近的数据中，我们在药物激活β-AR的药物激活后，发现中值穿孔路径突触的潜力提高。 β-ar功能在上下文中的这种上调NA纤维损失可能会驱动增强的LTP和掩模疾病早期学习和记忆的缺陷。当前的提议将检验以下假设 AD中海马去甲肾上腺素能的功能受到了由LC-NA细胞的异常刺激而受损进行性p-tau积累和通过NA神经支配，这两者在卵巢切除术中都会更糟女性，受O-Glcnacylation的保护。我们将在海马和基因座，海马依赖性行为，药理学，生物化学和O-GLCNAC生物学测试这个创新的假设。成果将为液晶损伤在AD中的作用提供新的启示，并将铺设地面针对针对LC甚至O-Glcnacylation的治疗策略的工作。