Background: Emerging evidence demonstrates association of Alzheimer's disease (AD) with impaired delivery of blood oxygen and nutrients to and throughout the brain. The cerebral circulation plays multiple roles underscoring optimal brain perfusion and cognition entailing moment-to-moment blood flow control, vascular permeability, and angiogenesis. With currently no effective treatment to prevent or delay the progression of AD, cerebrovascular microRNA (miRNA) markers corresponding to post-transcriptional regulation may distinguish phases of AD.
Objective: We tested the hypothesis that cerebrovascular miRNA expression profiles indicate developmental stages of AD pathology.
Methods: Total RNA was isolated from total brain vessel segments of male and female 3xTg-AD mice [young, 1-2 mo; cognitive impairment (CI), 4-5 mo; extracellular amyloid-β plaques (Aβ), 6-8 mo; plaques+neurofibrillary tangles (AβT), 12-15 mo]. NanoString technology nCounter miRNA Expression panel for mouse was used to screen for 599 miRNAs.
Results: Significant (p < 0.05) downregulation of various miRNAs indicated transitions from young to CI (e.g., let-7g & miR-1944, males; miR-133a & miR-2140, females) and CI to Aβ (e.g., miR-99a, males) but not from Aβ to AβT. In addition, altered expression of select miRNAs from overall Pre-AD (young + CI) versus AD (Aβ+ AβT) were detected in both males (let-7d, let-7i, miR-23a, miR-34b-3p, miR-99a, miR-126-3p, miR-132, miR-150, miR-151-5p, miR-181a) and females (miR-150, miR-539). Altogether, at least 20 cerebrovascular miRNAs effectively delineate AD versus Pre-AD pathology.
Conclusion: Using the 3xTg-AD mouse model, these data demonstrate that cerebrovascular miRNAs pertaining to endothelial function, vascular permeability, angiogenesis, inflammation, and Aβ/tau metabolism can track early development of AD.
Keywords: 3xTg-AD; cerebrovasculature; non-coding RNAs; sex differences.