Region-Specific Vulnerability of the Lewy Body Dementia's Brain

路易体痴呆症大脑的区域特异性脆弱性

• 批准号: 10291642
• 负责人: Tae-In Kam
• 金额: $ 66.43万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10291642
• 关键词: Affect; Alzheimer' s Disease; Amino Acids; Animal Model; Area; Astrocytes; Biochemical; Bioinformatics; Biological Models; Braak' s hypothesis; Brain; Brain region; Cells; Cerebellum; Complex; Data; Dementia; Development; Disease; Dissection; Event; Exhibits; Exposure to; Goals; Heterogeneity; Hippocampus (Brain); Human; Impaired cognition; Individual; Investigation; Label; Lead; Lewy Bodies; Lewy Body Dementia; Lewy neurites; Limbic System; Messenger RNA; Microdissection; Microglia; Modeling; Molecular; Neocortex; Nerve Degeneration; Neurites; Neurobehavioral Manifestations; Neurodegenerative Disorders; Neurons; Parkinsonian Disorders; Pathogenesis; Pathologic; Pathway interactions; Pattern; Physiology; Population; Process; Proteins; Proteome; Research Personnel; Role; Signal Pathway; Technology; Validation; alpha synuclein; brain tissue; cell behavior; cell type; entorhinal cortex; in vivo; insight; motor disorder; motor symptom; mouse model; neurodegenerative dementia; neuron loss; novel; physical separation; single cell analysis; synucleinopathy; transcriptome

REGION-SPECIFIC VULNERABILITY OF THE LEWY BODY DEMENTIA’S BRAIN PROJECT SUMMARY Lewy Body Dementia (LBD) is a progressive neurodegenerative disorder characterized by aggregation of the α- synuclein (α-syn) into intracellular inclusions called Lewy bodies (LB) and Lewy neurites (LN). This form of dementia belongs to a class of neurodegenerative diseases termed “synucleinopathies.” LBD is the most common neurodegenerative dementia after Alzheimer’s disease. In LBD, dementia usually proceeds to the onset of parkinsonian motor symptoms with neurobehavioral symptoms that may be accompanied by both cognitive and motoric dysfunction. While various misfolded oligomers, primarily constituted of α-syn, are associated with the development of dementia along with neuronal loss, there is still insufficient understanding of the pathogenesis process. Especially, particular brain areas such as the limbic system and neocortex are more vulnerable than other regions. Researchers have considered that the answer to this question will provide a key clue to understanding the pathogenesis mechanism. Inter-cellular crosstalk of neurons, microglia, and astrocytes results in complex physiologies and cellular behaviors, potentially leading to neuronal loss. Moreover, there is brain region-specific heterogeneity in cellular populations of neurons, microglia, and astrocytes that can contribute to the region-specific vulnerability of the LBD brain. Therefore, information on cell-type-specific and single-cell- specific proteome and transcriptome over multiple brain regions is indispensable for understanding this complex mechanism. To study this complex mechanism, the selection of the right aminal model that best recapitulates the human LBD pathogenesis process is crucial. The mouse model that recapitulates the Braak hypothesis would serve as the best animal model and we recently have generated this mouse model (gut-brain α-syn model) successfully by injecting α-syn to the gut. To study the regional vulnerability of LBD using the mouse model, we propose 1) to study region- and cell-type-specific proteome of the brain of the gut-brain α-syn model using BONCAT and xMD, 2) to study region- and single-cell-specific transcriptome of the brain of the gut-brain α-syn model using HiF-snRNAseq, 3) to perform integrative bioinformatic analysis and validate the affected pathways found in the mouse models using the human brain. Cell-type-specific proteome analysis and single-cell transcriptome analyses over multiple brain regions of the gut-brain α-syn model proposed in this application will enable us to identify region- and cell-type-specific signaling pathways that are involved in region-specific vulnerabilities to pathological α-syn. This novel information will contribute to a better understanding of LBD pathogenesis. Furthermore, these approaches can be expanded to studying pathogenesis mechanisms of other neurodegenerative diseases.

路易体痴呆患者大脑的区域特异性易损性 项目总结 路易体痴呆是一种进行性神经退行性疾病，其特征是α- 突触核蛋白(α-SYN)进入细胞内包涵体，称为路易小体(Lb)和路易神经节(LN)。这种形式的 痴呆症属于一种神经退行性疾病，被称为“联核病”。LBD是最多的 阿尔茨海默病后常见的神经退行性痴呆。在LBD中，痴呆症通常进展到发病 帕金森氏症的运动症状与神经行为症状可能同时伴有认知 和运动功能障碍。而各种错误折叠的低聚物，主要由α-SYN组成，与 痴呆症的发展伴随着神经元的丢失，目前对其发病机制仍认识不足 进程。特别是特定的大脑区域，如边缘系统和新皮质，比 其他地区。研究人员认为，这个问题的答案将为 了解其发病机制。神经元、小胶质细胞和星形胶质细胞的细胞间串扰 在复杂的生理和细胞行为中，可能导致神经元丢失。此外，还有大脑 神经元、小胶质细胞和星形胶质细胞群体中的区域特异性异质性可能有助于 LBD大脑的特定区域脆弱性。因此，关于特定细胞类型和单个细胞的信息- 多个大脑区域的特定蛋白质组和转录组对于理解这种复合体是必不可少的。 机制。为了研究这种复杂的机制，选择最能概括的正确的氨基模型 人类LBD的发病过程是至关重要的。重述布拉克假说的小鼠模型 作为最好的动物模型，我们最近建立了这个小鼠模型(肠道-脑α-SYN模型) 成功地将α-syn注射到肠道中。为了使用小鼠模型研究LBD的区域性脆弱性，我们 建议1)研究肠脑α-SYN模型脑内区域和细胞类型的特异性蛋白质组 BONCAT和xMD，2)研究肠脑α-Synn脑的区域和单细胞特异性转录组 使用HIF-SnRNAseq的模型，3)进行综合生物信息学分析并验证受影响的通路 在使用人脑的小鼠模型中发现。细胞类型特异性蛋白质组分析与单细胞 在本申请中提出的肠-脑α-SYN模型的多个脑区的转录组分析将 使我们能够识别区域和细胞类型特定的信号通路，这些信号通路涉及区域特定的 对病理性α-SYN的漏洞。这一新颖的信息将有助于更好地理解LBD 发病机制。此外，这些方法还可以扩展到研究其他疾病的发病机制。 神经退行性疾病。