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).

概括进行性核上麻痹（PSP）是一种令人衰弱的疾病区域以及严重的精神和运动缺陷。 PSP通常被误诊为帕金森氏病（率为50％）而且没有药物可以帮助PSP患者。患有PSP的人的预期寿命仅为6 - 8年，暗示症状学明显时，神经退行性已经远先进。因此，需要i）提高诊断的准确性，ii）找到生物标志物或行为缺陷早于症状，iii）找到治疗剂。为了促进这些目标，我们需要了解1）在大脑内部进行疾病起源的地方，2）脱离农产品时的神经途径，哪些神经途径症状和3）发病机理的地形进展。基于强大的初步数据，我们提出tau蛋白在胆碱能花梗中的积累（PPT）神经元中的积累后脑将在PSP影响的大脑区域中产生TAU聚集体，从无病状态发展到 PSP状的末端阶段，并产生类似PSP的行为不足缺陷）。为了在大鼠中产生类似PSP的病理学胆碱能PPT神经元中PSP（1N4R）占主导地位的Tau蛋白的同工型。五个月后感染，该模型与PSP一致：i）胆碱能神经元的丧失，ii）nigra的丧失多巴胺能神经元，iii）增加的磷酸化tau阳性神经元数量增加反射不足和V）运动缺陷。将tau蛋白过表达的动物与那些以5个月的间隔进行良性蛋白质的过表达，直到老年。我们将完成广泛的验尸组织化学分析，磁共振成像（MRI），REM睡眠记录和行为测试（例如认知和运动）以确定病理是否发展到疾病与后期PSP一致。一旦确定tau在胆碱能PPT神经元中的积累就足以产生迟到类似PSP的病理和行为缺陷，未来的工作将包括：1）确定策略改善症状和疾病进展，2）发现早期疾病发作的标记，3）分子机械研究（例如，特定靶标的敲低）。