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目标。突触 功能障碍和丢失通常先于神经元的退化，并且是 几种神经退行性疾病，包括路易体病、痴呆症。我们的预赛 数据显示，脑鞘糖脂升高后，补体系统被激活， 它们参与了路易体痴呆和相关疾病的病理生理学。入内 这项提案中概述的活体实验确定了补体激活，即免疫系统 以及路易体型痴呆的突触神经变性。此外，在这些方面 在临床前动物模型中，抑制补体途径的认知效应将是 下定决心。 我们特别假设(1)C1q和补体途径参与突触 突触参与的实验性路易体痴呆模型的功能障碍和丢失 退变和炎症反应是退变前的关键特征，以及(2)新颖 稳定的长效反义寡核苷酸能有效降低C1qA和C3 实验性路易体痴呆模型。这些实验将解决C1q和C1q是否 C3参与皮质和海马神经元的退化，使用(A)全脑 人Thy1α-突触核蛋白过表达，(B)区域aav人α-突触核蛋白表达，以及 (C)全身和脑内鞘糖脂诱导的α-突触核病和炎症 GbaD409V敲击小鼠。认知行为分析包括新的对象识别任务和 Y型迷宫。在实验性路易体痴呆模型中通过外周和中枢基因敲除 实验的设计也是为了区分C1q和C3在 消除大脑中的突触(通过大脑反义寡核苷酸靶向)和 可能需要的吞噬功能和全身影响(通过转基因敲除)。 研究补体通路调节器介导的突触丢失是一种范式 为了解路易小体和海马神经元退行性变 相关痴呆症。这些发现将影响对以下疾病的理解和治疗选择 潜在控制补体介导的突触消除和神经元变性 患有路易体痴呆症。

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.