Prevention of complement and immune-mediated Lewy body dementia

预防补体和免疫介导的路易体痴呆

基本信息

批准号：
10408001
负责人：
PENELOPE Jane HALLETT
金额：
$ 56.38万
依托单位：
MCLEAN HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-15 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10408001
关键词：
Address Alzheimer&apos s Disease Alzheimer&apos s disease model Amyloid beta-Protein Animal Model Animals Antisense Oligonucleotides Axon Behavioral Behavioral Assay Brain C1q deficiency Clinical Cognitive Cognitive deficits Complement Complement 1q Complement Activation Data Dementia Development Disease Experimental Models Exposure to Frontotemporal Dementia Functional disorder Glycosphingolipids Goals Hippocampus (Brain)Human Human Cell Line Immune Immune system Impaired cognition In Vitro Inflammation Inflammatory Response Injections Intervention Knock-in Mouse Knock-out Lewy Bodies Lewy Body Dementia Lewy Body Disease Measures Mediating Mediator of activation protein Memory impairment Messenger RNA Modeling Mus Mutation Neonatal Nerve Degeneration Neurodegenerative Disorders Neurons Oligonucleotides Pathology Peripheral Phagocytes Pre-Clinical Model Prevention Production Proteins RNA Splicing Reverse Transcriptase Polymerase Chain Reaction Role Somatotype Synapses Testing Therapeutic Time Transfection Transgenic Organisms Ubiquitin Virus alpha synuclein complement pathway complement system design experimental study in vitro testing in vivo in vivo Model knock-down mRNA Precursor neuroinflammation neuroprotection neurotoxicity normal aging novel object recognition overexpression pre-clinical prevent response synucleinopathy tau aggregation

项目摘要

Synapses and axons are targets of inflammation-induced neurodegeneration. Synaptic dysfunction and loss usually precedes degeneration of the neurons, and are early features of several neurodegenerative diseases including Lewy body disease dementia. Our preliminary data show that the complement system is activated after elevation of brain glycosphingolipids, which are involved in the pathophysiology of Lewy body dementia and related disorders. The in vivo experiments outlined in this proposal determine complement activation, the immune system and synaptic neurodegeneration in dementia of the Lewy body type. In addition, in these preclinical animal models, the cognitive effects of inhibiting the complement pathway will be determined. We specifically hypothesize that (1) C1q and the complement pathway is involved in synaptic dysfunction and loss in experimental Lewy body dementia models in which synaptic degeneration and inflammatory response are key pre-degenerative features, and (2) novel stabilized, long-acting antisense oligonucleotides can effectively reduce C1qA and C3 in experimental Lewy body dementia models. These experiments will address whether C1q and C3 are involved in the degeneration of cortical and hippocampal neurons using (a) global brain human Thy1 α-synuclein overexpression, (b) regional AAV human α-synuclein expression, and (c) systemic and brain glycosphingolipid-induced α-synucleinopathy and inflammation using GbaD409V knockin mice. Cognitive behavioral assays include novel object recognition tasks and Y-maze. By peripheral and central knockout in experimental Lewy body dementia models these experiments are also designed to distinguish between the local role of C1q and C3 in eliminating synapses in the brain (by brain antisense oligonucleotide targeting) and the potentially needed phagocytic function and systemic influence (by transgenic knockout). Investigating synaptic loss mediated by modulators of the complement pathway is a paradigm for understanding cortical and hippocampal neuron degeneration in models of Lewy body and related dementias. The findings will impact the understanding and therapeutic options to potentially control complement-mediated elimination of synapses and degeneration of neurons in Lewy body dementia.

突触和轴突是炎症引起的神经变性的靶标。突触功能障碍和损失通常是神经元变性之前的，并且是几种神经退行性疾病，包括Lewy身体疾病痴呆。我们的初步数据表明，在脑糖脂脂的升高后，完成系统会被激活，与Lewy身体痴呆症和相关疾病的病理生理有关。 in 该提案中概述的体内实验确定了完成激活，免疫系统和Lewy体型痴呆中的突触神经退行性。另外，在这些临床前动物模型，抑制完成途径的认知作用将是决定。我们特别假设（1）C1Q和补体途径参与突触突触的实验性路易体痴呆模型的功能障碍和损失退化和炎症反应是关键的分离前特征，（2）新颖稳定的长效反义寡核苷酸可以有效地减少C1QA和C3 实验性路易人身体痴呆模型。这些实验将解决C1Q和 C3使用（a）全球大脑参与皮质和海马神经元的变性人thy1α-突触核蛋白的过表达，（b）区域AAV人α-突触核蛋白的表达和（c）使用全身性和脑糖脂脂诱导的α-突触核病和使用炎症 GBAD409V敲击小鼠。认知行为分析包括新颖的对象识别任务和 Y迷宫。通过实验性路易体痴呆中的外围和中央敲除这些模型实验还旨在区分C1Q和C3在中的局部作用消除大脑中的突触（通过大脑反义寡核苷酸靶向）和潜在需要的吞噬功能和全身影响（通过转基因敲除）。调查完成途径的调节器介导的突触损失是一个范式了解路易体模型中的皮质和海马神经元变性相关痴呆症。这些发现将影响理解和治疗选择潜在控制完全介导的突触消除和神经元的变性在路易的身体痴呆症中。

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Viral-like TLR3 induction of cytokine networks and α-synuclein are reduced by complement C3 blockade in mouse brain.

DOI：
10.1038/s41598-023-41240-z
发表时间：
2023-09-13
期刊：
Scientific reports
影响因子：
4.6
作者：
通讯作者：

Loss of Lipid Carrier ApoE Exacerbates Brain Glial and Inflammatory Responses after Lysosomal GBA1 Inhibition.

DOI：
10.3390/cells12212564
发表时间：
2023-11-02
期刊：
Cells
影响因子：
6
作者：
通讯作者：

Glycosphingolipid metabolism and its role in ageing and Parkinson's disease.

DOI：
10.1007/s10719-021-10023-x
发表时间：
2022-03
期刊：
Glycoconjugate journal
影响因子：
3
作者：
Wallom KL;Fernández-Suárez ME;Priestman DA;Te Vruchte D;Huebecker M;Hallett PJ;Isacson O;Platt FM
通讯作者：
Platt FM