Tau accumulation in the pedunculopontine tegmentum as an early node in Progressive Supranuclear Palsy pathogenesis

桥脚被盖中 Tau 蛋白的积累是进行性核上性麻痹发病机制的早期节点

基本信息

批准号：
10209162
负责人：
Stewart Donaldson Clark
金额：
$ 180.84万
依托单位：
STATE UNIVERSITY OF NEW YORK AT BUFFALO
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-01 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10209162
关键词：
3-Dimensional Acoustics Acute Age Aging Alzheimer&apos s Disease Animals Area Attentional deficit Autopsy Behavior Behavioral Benign Biochemical Biological Biological Markers Brain Brain region Characteristics Clinical Cognitive Cognitive deficits Collaborations Data Deltastab Dependovirus Diagnosis Disease Disease Marker Disease Progression Electroencephalography Event Exhibits Female Future Goals Histologic Histopathology Human Image Impaired cognition Infection Injections Knowledge Lateral Learning Lesion Life Expectancy Magnetic Resonance Imaging Magnetic Resonance Spectroscopy Measures Methods Midbrain structure Modeling Molecular Molecular Profiling Motor Nerve Degeneration Neural Pathways Neurodegenerative Disorders Neurons Onset of illness Parkinson Disease Pathogenesis Pathologic Pathology Patients Pharmaceutical Preparations Pharmacotherapy Physical therapy Pontine structure Population Process Progressive Supranuclear Palsy Protein Isoforms Protein Overexpression Proteins Psyche structure REM Sleep Rattus Reflex action Reproducibility Resolution Sensory Sleep Deprivation Slow-Wave Sleep Structure Substantia nigra structure Suggestion Symptoms Syndrome Tauopathies Testing Thalamic structure Therapeutic Time Tissues Universities Ventricular Wakefulness Work base behavior test cholinergic cholinergic neuron clinically relevant cohort diagnostic accuracy dopaminergic neuron drug discovery entorhinal cortex genetically engineered virus hindbrain human old age (65+)hyperphosphorylated tau improved in vivo imaging knock-down male motor deficit motor disorder neural network overexpression pedunculopontine tegmentum pre-clinical programs protein aggregation proteostasis selective expression tau Proteins tau aggregation tau dysfunction tau mutation

项目摘要

Summary Progressive Supranuclear Palsy (PSP) is a debilitating disease with aggregates of tau protein in multiple brain areas and severe mental and motor deficits. PSP is often misdiagnosed as Parkinson's Disease (rate of 50%) and there are no drugs that help PSP sufferers. Those with PSP have a life expectancy of only 6-8 years, suggestive that the neurodegeneration is already far advanced when symptomology becomes evident. Therefore, there is a need to i) increase the accuracy of diagnosis, ii) find biomarkers or behavioral deficits that predate the symptoms, and iii) find therapeutics. To facilitate these goals, we need to understand 1) from where within the brain does the disease originate, 2) which neural pathways when degenerated produce which symptoms, and 3) the topographical progression of pathogenesis. Based on strong preliminary data, we propose that the accumulation of tau protein in cholinergic pedunculopontine tegmentum (PPT) neurons in the hindbrain will produce tau aggregates in brain regions impacted in PSP, progress from a disease-free state to a PSP-like end stage, and produce PSP-like behavioral deficits (e.g. dysexecutive frontal syndrome and motor deficits). To produce PSP-like pathology in rats we use a genetically engineered virus to selectively over-express the isoform of the tau protein that predominates in PSP (1N4R) in cholinergic PPT neurons. At 5 months post- infection, the model is consistent with PSP: i) a loss of cholinergic neurons, ii) loss of substantia nigra dopaminergic neurons, iii) increased number of hyperphosphorylated tau-positive neurons, iv) acoustic startle reflex deficit, and v) motor deficits. Animals with tau protein over-expression will be compared to those that have the over-expression of a benign protein at 5 month intervals until old age. We will complete extensive postmortem histochemical analysis, Magnetic Resonance Imaging (MRI), REM sleep recordings, and behavioral testing (e.g. cognitive & motor) to establish whether the pathology progresses to a condition consistent with late-stage PSP. Once it is established that accumulation of tau in the cholinergic PPT neurons is sufficient to produce late stage PSP-like pathology and behavior deficits, future work would include: 1) identifying strategies that ameliorate symptomology and disease progression, 2) the discovery of early markers of disease onset, and 3) molecular mechanistic studies (e.g. knockdown of specific targets).

概括进行性核上性麻痹 (PSP) 是一种使人衰弱的疾病，多脑中 tau 蛋白聚集区以及严重的精神和运动缺陷。 PSP 经常被误诊为帕金森病（误诊率为 50%）并且没有药物可以帮助 PSP 患者。患有PSP的人的预期寿命只有6-8年，当症状变得明显时，表明神经变性已经很严重了。因此，有必要 i) 提高诊断的准确性，ii) 找到生物标志物或行为缺陷在症状出现之前，iii) 找到治疗方法。为了实现这些目标，我们需要了解 1) 疾病起源于大脑的哪个部位，2) 哪些神经通路退化时会产生哪些神经通路症状，3) 发病机制的局部进展。基于强有力的初步数据，我们提出tau蛋白在胆碱能脚桥被盖（PPT）神经元中的积累后脑将在 PSP 影响的大脑区域产生 tau 蛋白聚集，从无病状态进展到类似 PSP 的终末阶段，并产生类似 PSP 的行为缺陷（例如执行不良额叶综合征和运动障碍）赤字）。为了在大鼠中产生类似 PSP 的病理学，我们使用基因工程病毒选择性地过度表达在胆碱能 PPT 神经元的 PSP (1N4R) 中占主导地位的 tau 蛋白亚型。 5个月后感染，该模型与 PSP 一致：i) 胆碱能神经元损失，ii) 黑质损失多巴胺能神经元，iii) 过度磷酸化 tau 阳性神经元数量增加，iv) 声惊吓反射缺陷，以及 v) 运动缺陷。 tau 蛋白过度表达的动物将与那些每隔 5 个月就会过度表达一种良性蛋白质，直至老年。我们将完成广泛的尸检组织化学分析、磁共振成像 (MRI)、快速眼动睡眠记录和行为测试（例如认知和运动）以确定病理是否进展为某种状况与后期PSP一致。一旦确定胆碱能 PPT 神经元中 tau 蛋白的积累足以产生晚期阶段 PSP 样病理和行为缺陷，未来的工作将包括：1）确定策略改善症状和疾病进展，2) 发现疾病发作的早期标志物，以及 3) 分子机制研究（例如特定靶标的敲低）。