CTBS通过E/I平衡调控PVS-ISF通道AQP4极性表达对AD小鼠Aβ清除和认知功能的作用及机制

Aβ清除障碍造成的沉积和神经连接损伤是AD认知功能损害的关键因素。血管旁间隙-组织间液（PVS-ISF）通道是清除Aβ最主要的途径，星形胶质细胞（AC）的水通道蛋白4（AQP4）是控制该通道的闸门。我们前期研究发现PVS-ISF通道转运功能与GLU/GABA-AC连接兴奋抑制（E/I）平衡相关；连续θ爆发式刺激（cTBS）能够恢复AQP4极性表达而提高PVS-ISF通道转运速率。据此我们设想：cTBS可以通过调节GLU/GABA-AC连接E/I平衡，对AQP4极性表达产生影响，从而调控PVS-ISF通道，促进Aβ清除，改善认知功能。本项目拟采用双光子活体成像和双通道膜片钳技术相结合，利用不同强度cTBS对AD小鼠进行干预，阐明cTBS通过调控E/I平衡对AQP4极性表达和PVS-ISF通道外流转运Aβ的作用机制。这不仅在探讨cTBS的中枢调控机制上具有创新，还为认知障碍提供了新的治疗策略。

With the process of aging population and Alzheimer's disease (AD), the age-related cognitive impairment for amyloid beta (Aβ) plaque has brought a heavy burden to families and society. Recently, Aβ plaque formation is hypothesized to be caused by an imbalance between Aβ production and clearance, which is mainly due to a decrease in Aβ clearance. Aβ could be cleared through the different ways. Paravascular space (PVS), the brain-wide network, has been demonstrated to efficiently facilitate the clearance of interstitial solutes, including neuronally produced Aβ, from the brain interstitial fluid (ISF). Moreover, A loss of Aquaporin-4 (AQP4) polarization in perivascular astrocytic endfeet such as occurs in the aging brain and AD, may result in PVS-ISF pathway breakdown. AQP4 is a water channel expressed on astrocytic (AC) endfeet in the brain. Emerging data suggest that AQP4 may be implicated in the PVS-ISF pathway and may be involved in the clearance of Aβ in AD. In our previous study, the results have showed that Glu/GABA could influence the Aβ clearance through the PVS-ISF pathway may be an interesting target to relieve the Aβ burden in the brain. Generally, brain function depends on the homeostatic regulation between excitation and inhibition balance (E/I balance). Whilst most studies report that GABAergic neurons were the prime source of modulating E/I balance in brain. Indeed, GABA is AQP4-dependent in their modulation roles. Based on the E/I balance through GABA-cell-mediated inhibition theory, we hypothesize that continuous theta burst stimulation (cTBS), multiple bursts delivered at theta frequency (3-7Hz), should be an important strategy in the treatment of E/I imbalance in brain lesions. However, the role of cTBS in modulation of E/I balance of Glu/GABA-AC connection is less understood. Thus, we hypothesize that precision navigation for targeting AQP4-dependent PVS-ISF pathway via cTBS stimulation should be an important strategy not only in the treatment of Aβ clearance but also in the plasticity of injury induced by brain aging. In this study, we should investigate the effect of cTBS-induced E/I balance through AQP4 polarization in PVS-ISF pathway on Aβ clearance and cognitive function in mouse models. Indeed, we can demonstrate that (1) the relationship between E/I imbalance, gamma synchrony, and cTBS-induced in vivo YFP mice; (2) the AQP4 polarization across the maintenance of E/I balance through cTBS-induced; (3) the specific facet of cTBS-induced neural E/I balance in AD. These findings will be put in context by investigation of precision brain aging and neurodegenerative diseases rehabilitation medicine via cTBS through data-driven analysis and theoretical models.