Tabassum Nishat I, Selvaraji Sharmelee, Fan Yibo, Lim Vernise Jt, Cheng Xiangru, Peng Xiangyuan, Arora Aayushi, Rajeev Vismitha, Ratcliffe Julian, Johnson Chad J, Datta Keshava K, Lowe Rohan, Ebrahimi Mansour, Dinh Quynh Nhu, De Silva T Michael, Sobey Christopher G, Wong Peiyan, Weng Eddie Feng-Ju, Jo Dong-Gyu, Chen Christopher P, Lai Mitchell K P, Arumugam Thiruma V
Department of Microbiology, Anatomy, Physiology and Pharmacology, School of Agriculture, Biomedicine and Environment, La Trobe University, Melbourne, Australia.
La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Australia.
Theranostics. 2025 Jul 25;15(16):8429-8450. doi: 10.7150/thno.119422. eCollection 2025.
Vascular dementia (VaD), driven by chronic cerebral hypoperfusion (CCH), leads to synaptic degeneration and cognitive decline, yet mechanisms linking vascular dysfunction to synaptic loss remain unclear. Intermittent fasting (IF) has emerged as a potential intervention, but its effects on synaptic integrity in VaD are unknown. This study aims to investigate the effects of IF against synaptic degeneration and cognitive impairment induced by CCH. Methods: Bilateral common carotid artery stenosis (BCAS) was employed to induce chronic CCH by placing 0.18 mm micro-coils around each common carotid artery in mice. To assess temporal differences, the coils remained in place for 1, 7, 14, or 30 days. IF was implemented for 16 hours daily over three months prior to BCAS induction. Cognitive impairment was evaluated using the Barnes maze test. White matter lesions (WMLs) and neuronal loss were assessed using Luxol fast blue and cresyl violet staining, respectively. Immunoblotting and immunohistochemistry were performed to quantify synaptic protein levels. Synaptic integrity was examined using transmission electron microscopy. Proteomic analysis of the hippocampus was conducted to investigate molecular adaptations to IF following CCH. We demonstrate that a 16-hour IF regimen preserves cognitive function and synaptic density despite persistent hypoperfusion. Behavioral assays revealed that IF prevented spatial memory deficits in BCAS mice, while electron microscopy confirmed synaptic preservation without altering baseline architecture. Surprisingly, key synaptic protein levels remained unchanged, suggesting IF protects synaptic function rather than abundance. Proteomic profiling revealed dynamic hippocampal adaptations under IF, including upregulation of synaptic stabilizers, enhanced GABAergic signaling, and suppression of neuroinflammatory mediators. CCH induced microglial engulfment of synapses, suggesting a role in complement-mediated synaptic pruning. Temporal pathway analysis revealed IF's multi-phase neuroprotection: early synaptic reinforcement, mid-phase metabolic optimization, and late-phase suppression of chronic neuroinflammation. These findings establish IF as a potent modulator of synaptic resilience in VaD, acting through coordinated preservation of synaptic structure, inhibition of inflammatory synapse loss, and metabolic reprogramming. Our results highlight IF's potential as a non-pharmacological strategy to combat vascular cognitive impairment by targeting the synaptic vulnerability underlying dementia progression.
血管性痴呆（VaD）由慢性脑灌注不足（CCH）引发，会导致突触退化和认知能力下降，但血管功能障碍与突触丧失之间的联系机制仍不清楚。间歇性禁食（IF）已成为一种潜在的干预措施，但其对VaD中突触完整性的影响尚不清楚。本研究旨在探究间歇性禁食对由慢性脑灌注不足诱导的突触退化和认知障碍的影响。方法：采用双侧颈总动脉狭窄（BCAS），通过在小鼠每条颈总动脉周围放置0.18毫米的微线圈来诱导慢性脑灌注不足。为了评估时间差异，线圈放置1、7、14或30天。在诱导BCAS之前的三个月里，每天进行16小时的间歇性禁食。使用巴恩斯迷宫试验评估认知障碍。分别使用卢氏固蓝和甲酚紫染色评估白质病变（WMLs）和神经元损失。进行免疫印迹和免疫组织化学以量化突触蛋白水平。使用透射电子显微镜检查突触完整性。对海马体进行蛋白质组分析，以研究慢性脑灌注不足后对间歇性禁食的分子适应性。我们证明，尽管存在持续的灌注不足，16小时的间歇性禁食方案仍能保留认知功能和突触密度。行为分析表明，间歇性禁食可预防BCAS小鼠的空间记忆缺陷，而电子显微镜证实突触得以保留，且未改变基线结构。令人惊讶的是，关键突触蛋白水平保持不变，这表明间歇性禁食保护的是突触功能而非其丰度。蛋白质组分析揭示了间歇性禁食条件下海马体的动态适应性变化，包括突触稳定剂上调、γ-氨基丁酸能信号增强以及神经炎症介质受到抑制。慢性脑灌注不足诱导小胶质细胞吞噬突触，表明其在补体介导的突触修剪中发挥作用。时间通路分析揭示了间歇性禁食的多阶段神经保护作用：早期突触强化、中期代谢优化以及晚期对慢性神经炎症的抑制。这些发现确立了间歇性禁食作为血管性痴呆中突触弹性的有效调节因子的地位，其作用机制是通过协同保护突触结构、抑制炎症性突触丧失以及代谢重编程。我们的研究结果凸显了间歇性禁食作为一种非药物策略的潜力，即通过针对痴呆进展背后的突触易损性来对抗血管性认知障碍。
