Dataset Information

Intermittent Fasting Reprograms the Brain Proteome to Prevent Synaptic Degeneration and Cognitive Impairment in Vascular Dementia

ABSTRACT: 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. Using the bilateral common carotid artery stenosis (BCAS) mouse model, we demonstrate that a 16-hour IF regimen preserves cognitive function and cortical 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, synaptic protein levels remained unchanged, suggesting IF protects synaptic function rather than abundance. Proteomic profiling uncovered dynamic hippocampal adaptations under IF, including upregulation of synaptic stabilizers, enhanced GABAergic signaling, and suppression of neuroinflammatory mediators. IF also attenuated microglial engulfment of synapses, indicating modulation of complement-mediated 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.

INSTRUMENT(S):

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Hippocampus

DISEASE(S): Vascular Dementia

SUBMITTER: Nishat Tabassum

LAB HEAD: Thiruma V. Arumugam

PROVIDER: PXD064537 | Pride | 2025-09-08

REPOSITORIES: Pride

ACCESS DATA

Dataset's files

Source:

			Action	DRS
	All_3_batches_combined_search-lib.tsv.speclib	Tabular
	All_3_batches_combined_search.gg_matrix.tsv	Tabular
	All_3_batches_combined_search.pdf	Pdf
	All_3_batches_combined_search_log.txt	Txt
	All_3_batches_combined_search_pg_matrix.tsv	Tabular

Items per page:

1 - 5 of 15

Publications

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

Tabassum Nishat I NI Selvaraji Sharmelee S Fan Yibo Y Lim Vernise Jt VJ Cheng Xiangru X Peng Xiangyuan X Arora Aayushi A Rajeev Vismitha V Ratcliffe Julian J Johnson Chad J CJ Datta Keshava K KK Lowe Rohan R Ebrahimi Mansour M Dinh Quynh Nhu QN De Silva T Michael TM Sobey Christopher G CG Wong Peiyan P Weng Eddie Feng-Ju EF Jo Dong-Gyu DG Chen Christopher P CP Lai Mitchell K P MKP Arumugam Thiruma V TV

Theranostics 20250725 16

<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 ...[more]

PMID: 40860138

Similar Datasets

Project description:Alzheimer’s disease (AD) and vascular dementia (VaD) are the two most common forms of dementia, neither of which can be effectively treated. There is growing evidence on vascular contributions to cognitive impairment and dementia such as AD, but their pathogenic molecular links are not defined yet. Notably, neurofibrillary tangles made of hyperphosphorylated tau (P-tau) are a hallmark lesion of AD, but are not found in VaD. Although brain ischemia induces some tau changes and tau knockout reduces stroke-induced acute brain damage, little is known about the role of tau in mediating progression from vascular insufficiency to later development of VaD. Cis P-tau is a pre-tangle pathology in AD and an early driver of neurodegeneration resulting from brain injury, but its role in AD treatment or in VaD is unknown. Here we identify cis P-tau as an antibody-neutralizable major common early driver of AD and VaD. We show that cis P-tau elimination using cis antibody not only prevents, but also treats AD-like neurodegeneration and memory loss in a hTau mouse model of AD. Purified cis P-tau causes and spreads neurodegeneration with behavioral changes when injected into wild-type mouse brains, but is prevented by cis antibody. Surprisingly, we also find robust cis P-tau with no evidence of tau tangles in human VaD brains and a mouse model of chronic cerebral hypoperfusion that mimics key aspects of clinical VaD. Cis mAb treatment of hypoperfusive mice for 1 or 6 months blocks VaD-like neuropathological and functional outcomes. Single-cell transcriptomic profiling reveals that cerebral hypoperfusion induces numerous global changes in diverse brain cells including those of human AD brains. Remarkably, ~90% of these global changes are fully recovered with cis antibody, correlating with tau expression in cells. Thus, cis P-tau is a major common early driver of AD and VaD, and cis antibody has a potential role in the early detection, prevention and treatment of these devastating diseases.