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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.

突触和轴突是炎症性神经变性的靶点。突触

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：

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

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