Prevention of complement and immune-mediated Lewy body dementia

突触和轴突是炎症诱导的神经变性的靶点。突触 功能障碍和损失通常先于神经元的变性，并且是神经元变性的早期特征。 几种神经退行性疾病，包括路易体病痴呆。我们的初步 数据显示补体系统在脑鞘糖脂升高后被激活， 其参与路易体痴呆和相关病症的病理生理学。的in 在这个建议中概述的体内实验确定补体激活，免疫系统 和路易体痴呆中的突触神经变性。此外，在这些 在临床前动物模型中，抑制补体途径的认知效果将被证实。 测定 我们特别假设：（1）C1 q和补体通路参与了突触 在实验性路易体痴呆模型中， 变性和炎症反应是关键的变性前特征，和（2）新的 稳定的长效反义寡核苷酸可以有效地减少C1 qA和C3， 路易体痴呆模型这些实验将解决C1 q和 C3参与皮质和海马神经元的变性，使用（a）全球脑 人Thy 1 α-突触核蛋白过表达，（B）区域性AAV人α-突触核蛋白表达，和 (c)使用糖鞘脂诱导的全身和脑α-突触核蛋白病和炎症 GbaD 409 V基因敲入小鼠。认知行为分析包括新的物体识别任务， Y型迷宫通过在实验性路易体痴呆模型中的外周和中枢敲除， 实验也被设计来区分C1 q和C3的局部作用， 消除脑中的突触（通过脑反义寡核苷酸靶向）， 潜在需要的吞噬功能和系统影响（通过转基因敲除）。 研究补体途径调节剂介导的突触丢失是一个范例， 用于了解路易体模型中的皮质和海马神经元变性， 相关的痴呆症这些发现将影响对癌症的理解和治疗选择， 潜在地控制补体介导的突触消除和神经元变性 路易体痴呆症

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.