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Theranostics 2025; 15(16):8429-8450. doi:10.7150/thno.119422 This issue Cite

Research Paper

Intermittent fasting reprograms the brain proteome to prevent synaptic degeneration and cognitive impairment in vascular dementia

Nishat I. Tabassum^1,2,✉, Sharmelee Selvaraji^3,4, Yibo Fan^1,2, Vernise JT. Lim^1,2, Xiangru Cheng^1,2, Xiangyuan Peng^1,2, Aayushi Arora^1,2, Vismitha Rajeev⁵, Julian Ratcliffe⁶, Chad J. Johnson⁶, Keshava K. Datta⁷, Rohan Lowe⁷, Mansour Ebrahimi^1,2, Quynh Nhu Dinh^1,2, T Michael De Silva^1,2,8, Christopher G. Sobey^1,2,8,9, Peiyan Wong¹⁰, Eddie Feng-Ju Weng^11,12, Dong-Gyu Jo¹³, Christopher P. Chen⁵, Mitchell K.P. Lai⁵, Thiruma V. Arumugam^1,2,13,✉

1. Department of Microbiology, Anatomy, Physiology and Pharmacology, School of Agriculture, Biomedicine and Environment, La Trobe University, Melbourne, Australia.
2. La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Australia.
3. Research Laboratory of Electronics, Department of Materials Science and Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA.
4. McGovern Institute for Brain Research, Massachusetts Institute of Technology, Cambridge, MA, USA.
5. Memory Aging and Cognition Centre, Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
6. Bioimaging Platform, La Trobe University, Bundoora, VIC, Australia.
7. La Trobe University-Proteomics and Metabolomics Platform (LTU-PMP), La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Australia.
8. Centre for Cardiovascular Biology and Disease Research, La Trobe Institute for Molecular Sciences, La Trobe University, Bundoora, Victoria, 3086, Australia.
9. Baker Heart and Diabetes Institute, Melbourne, Victoria, 3004, Australia
10. Signature Research Programme in Neuroscience & Behavioural Disorders, Duke-NUS Medical School, Singapore.
11. Neuroscience and Brain Disease Centre, China Medical University, Taichung, Taiwan.
12. Graduate Institute of Biomedical Sciences, College of Medicine, China Medical University, Taichung, Taiwan.
13. School of Pharmacy, Sungkyunkwan University, Suwon, Republic of Korea.

✉ Corresponding authors: Thiruma V. Arumugam or Nishat I. Tabassum, La Trobe Institute for Molecular Science and Department of Microbiology, Anatomy, Physiology and Pharmacology, School of Agriculture, Biomedicine and Environment, La Trobe University, Bundoora, VIC, Australia. E-mail: g.arumugamedu.au; garriearumugamcom or N.Tabassumedu.au. More

Abstract

Rationale: 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.

Results: 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.

Conclusion: 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.

Keywords: intermittent fasting, vascular dementia, synaptic loss, cognitive impairment, neuronal death

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