Given the global aging trend and the rising challenge of Alzheimer's disease (AD), accumulating evidence identifies cerebral microvascular dysfunction as an early pathological event. Hence, elucidating the key molecular regulators of cerebral microvascular function is critical for developing early intervention strategies.
Objective
To identify key genes associated with cerebral microvascular dysfunction in early-stage AD based on transcriptomics and to investigate the competing endogenous RNA (ceRNA) network involving long non-coding RNA (lncRNA).
Methods
Immunofluorescence staining for CD31 was conducted on cerebral cortical sections from 1-month-old APP/PS1 and wild-type (WT) mice. Cerebral cortex and microvascular fractions were isolated for qPCR and western blot analysis of microvascular functional molecules. Following differential expression analysis, we performed functional and pathway enrichment, PPI network construction, ClueGo module analysis, and CFG prioritization to screen for core genes regulating cerebral microvascular function. A comprehensive ceRNA network was then established by integrating multi-database miRNA target predictions with RNA expression correlation data.
Results
One-month-old AD mice exhibited both reduced cerebral microvascular density and average vessel length, along with significant disruption in the expression of blood-brain-barrier proteins. Transcriptomic profiling identified 956 differentially expressed transcripts, including 539 lncRNAs, 412 mRNAs, and 5 miRNAs. By integrative bioinformatics analysis, we identified 11 hub genes primarily involved in vascular contraction and circadian regulation, and constructed a comprehensive ceRNA network comprising 7 mRNAs, 41 miRNAs, and 46 lncRNAs.
Conclusions
Our results reveal that early-stage AD is characterized by cerebral microvascular dysfunction, primarily mediated through impaired vascular contraction and disrupted circadian rhythm regulation.
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