Nishat I Tabassum, Sharmelee Selvaraji, Yibo Fan, Vernise Jt Lim, Xiangru Cheng, Xiangyuan Peng, Aayushi Arora, Vismitha Rajeev, Julian Ratcliffe, Chad J Johnson, Keshava K Datta, Rohan Lowe, Mansour Ebrahimi, Quynh Nhu Dinh, T Michael De Silva, Christopher G Sobey, Peiyan Wong, Eddie Feng-Ju Weng, Dong-Gyu Jo, Christopher P Chen, Mitchell K P Lai, Thiruma V Arumugam
{"title":"间歇性禁食重新编程脑蛋白质组以防止血管性痴呆的突触变性和认知障碍。","authors":"Nishat I Tabassum, Sharmelee Selvaraji, Yibo Fan, Vernise Jt Lim, Xiangru Cheng, Xiangyuan Peng, Aayushi Arora, Vismitha Rajeev, Julian Ratcliffe, Chad J Johnson, Keshava K Datta, Rohan Lowe, Mansour Ebrahimi, Quynh Nhu Dinh, T Michael De Silva, Christopher G Sobey, Peiyan Wong, Eddie Feng-Ju Weng, Dong-Gyu Jo, Christopher P Chen, Mitchell K P Lai, Thiruma V Arumugam","doi":"10.7150/thno.119422","DOIUrl":null,"url":null,"abstract":"<p><p><b>Rationale:</b> 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. <b>Results:</b> 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. <b>Conclusion:</b> 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.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 16","pages":"8429-8450"},"PeriodicalIF":13.3000,"publicationDate":"2025-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12374579/pdf/","citationCount":"0","resultStr":"{\"title\":\"Intermittent fasting reprograms the brain proteome to prevent synaptic degeneration and cognitive impairment in vascular dementia.\",\"authors\":\"Nishat I Tabassum, Sharmelee Selvaraji, Yibo Fan, Vernise Jt Lim, Xiangru Cheng, Xiangyuan Peng, Aayushi Arora, Vismitha Rajeev, Julian Ratcliffe, Chad J Johnson, Keshava K Datta, Rohan Lowe, Mansour Ebrahimi, Quynh Nhu Dinh, T Michael De Silva, Christopher G Sobey, Peiyan Wong, Eddie Feng-Ju Weng, Dong-Gyu Jo, Christopher P Chen, Mitchell K P Lai, Thiruma V Arumugam\",\"doi\":\"10.7150/thno.119422\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p><b>Rationale:</b> 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. <b>Results:</b> 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. <b>Conclusion:</b> 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.</p>\",\"PeriodicalId\":22932,\"journal\":{\"name\":\"Theranostics\",\"volume\":\"15 16\",\"pages\":\"8429-8450\"},\"PeriodicalIF\":13.3000,\"publicationDate\":\"2025-07-25\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12374579/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Theranostics\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.7150/thno.119422\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2025/1/1 0:00:00\",\"PubModel\":\"eCollection\",\"JCR\":\"Q1\",\"JCRName\":\"MEDICINE, RESEARCH & EXPERIMENTAL\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Theranostics","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.7150/thno.119422","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/1/1 0:00:00","PubModel":"eCollection","JCR":"Q1","JCRName":"MEDICINE, RESEARCH & EXPERIMENTAL","Score":null,"Total":0}
Intermittent fasting reprograms the brain proteome to prevent synaptic degeneration and cognitive impairment in vascular dementia.
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.
期刊介绍:
Theranostics serves as a pivotal platform for the exchange of clinical and scientific insights within the diagnostic and therapeutic molecular and nanomedicine community, along with allied professions engaged in integrating molecular imaging and therapy. As a multidisciplinary journal, Theranostics showcases innovative research articles spanning fields such as in vitro diagnostics and prognostics, in vivo molecular imaging, molecular therapeutics, image-guided therapy, biosensor technology, nanobiosensors, bioelectronics, system biology, translational medicine, point-of-care applications, and personalized medicine. Encouraging a broad spectrum of biomedical research with potential theranostic applications, the journal rigorously peer-reviews primary research, alongside publishing reviews, news, and commentary that aim to bridge the gap between the laboratory, clinic, and biotechnology industries.