前额叶皮质DA能轴突末梢丢失致PD伴执行功能障碍的机制研究

帕金森病伴执行功能障碍（PD-EDF）严重影响患者生活。据报道：PD-EDF患者的前额叶皮质（PFC）多巴胺（DA）信号减弱，这与DA能轴突末梢丢失有关，但机制不明。我们发现：PD-EDF患者血清溶血磷脂酰胆碱（LPC）异常升高；PD-EDF鼠的PFC小胶质活化、DA能末梢突触丢失增加。而突触前膜磷脂酰丝氨酸(PS)/C1q信号能介导小胶质对其吞噬。故推测：PD发展过程中，PFC升高的LPC激活小胶质，小胶质通过识别DA能突触前膜PS/C1q信号，将突触前成分吞噬，引起DA能轴突末梢丢失，致EDF发生。本项目拟先明确“PD-EDF、LPC升高、PFC的DA能轴突末梢丢失”的关系，后逐一证实PFC的DA能突触前膜在LPC诱导下形成PS/C1q信号、介导小胶质吞噬、DA能轴突末梢丢失、EDF的发生。从分子、突触、细胞、行为水平阐明PFC的DA能轴突末梢丢失的机制，为阻断PD-EDF提供新思路。

Parkinson's disease (PD) is thought to develop gradually over many years. Cognitive impairment is also common, with approximately 25% of PD patients without dementia having a mild cognitive impairment (MCI) and up to 80% of patients progressing to dementia eventually. In particular, executive dysfunction is the most frequently reported cognitive symptom among patients with PD. Executive functions are defined as the mental processes involved in adaptive behavior, new concepts, problem-solving, and planning. Parkinson’s disease with executive dysfunction (PD-EDF) patients may struggle to control and regulate their behaviors or perform tasks requiring attention and complex thinking. Executive dysfunction is thought to impact several daily life functions. Therefore, it has become the research hotspot of contemporary cognitive science and attracted much attention. However, the mechanism of PD-EDF remains unknown..Executive functions rely heavily on the integrity of the prefrontal cortex (PFC). We have previously observed that when PD-EDF occurs, the dopaminergic axon terminals of PFC are seriously lost. It was reported that the recognition and phagocytosis of synapses by activated microglia via phosphatidylserine (PS)/C1q signal of the presynaptic membrane of the axon terminals. Besides, our preliminary research observed that the lysophosphatidylcholine (LPC) level in the serum of PD-EDF patients was significantly increased, which may be a risk factor for PD occurrence. Some research reported LPC could activate central microglia cells and disrupt advanced brain functions. Furthermore, LPC's activated microglia could induce astrocyte (A1) polarization, with glial cell-derived neurotrophic factor (GDNF) synthesis and secretion decreased. Our preliminary research has found that progressive loss of dopaminergic synapses of PFC was identified with the gradual reduction of GDNF. Therefore, we put forward the hypothesis: PD-EDF may occur due to the increased LPC in the PFC, leading to microglia activation. Subsequently, activated microglia mediates the transformation of astrocytes to A1 type with reduced GDNF secretion, contributing to the formation of the PS/C1q signal of the dopaminergic presynaptic membrane. Microglia then recognizes the signal module and further engulfs the presynaptic element, contributing to the loss of axon endings of dopaminergic projection leading to EDF occurrence..The transmitter probe techniques, SPR technology, the PLA-doulink, touch screen analysis behavior will be used in our project. Firstly, LPC's explicit relationship abnormally elevated in PFC and PD patients' executive dysfunction will be determined. Then, we will further probe when the increased LPC in the PFC, the formation of PS/C1q signaling in the dopaminergic presynaptic membrane and relevant mechanism; PS/C1q signal mediates microglial phagocytosis; loss of DA axon terminals; and subsequent executive dysfunction. This project will focus on the mechanism of executive dysfunction from the "molecules, synapses, cells and behavior" level, which is the front line and hot issue in modern “Advanced Brain Function“ science. The exploration of origin and downstream result will be performed surrounding “the dopaminergic axon terminals of PFC seriously lost,” which will deepen the understanding of the biological mechanism of PD - EDF and help to find how to block the occurrence and progress of PD - EDF targets to provide new ideas.