Affiliations: Basic Sciences, Loma Linda University, Loma Linda, CA, USA
Correspondence:
[*]
Correspondence to: Erik J. Behringer, PhD, Department of Basic Sciences, 11041 Campus Street, Risley Hall, Loma Linda University, Loma Linda, CA 92350, USA. Tel.: +1 909 651 5334; Fax: +1 909 558 0119; E-mail: ebehringer@llu.edu.
Abstract: Background:Alzheimer’s disease (AD) is associated with impaired cerebral circulation which underscores diminished delivery of blood oxygen and nutrients to and throughout the brain. In the 3xTg-AD mouse model, we have recently found that > 10 cerebrovascular miRNAs pertaining to vascular permeability, angiogenesis, and inflammation (e.g., let-7d, miR-99a, miR-132, miR-133a, miR-151-5p, and miR-181a) track early development of AD. Further, endothelial-specific miRNAs (miR-126-3p, miR-23a/b, miR-27a) alter with onset of overall AD pathology relative to stability of smooth muscle/pericyte-specific miRNAs (miR-143, miR-145). Objective:We tested the hypothesis that cerebrovascular miRNAs indicating AD pathology share mRNA targets that regulate key endothelial cell functions such as angiogenesis, vascular permeability, and blood flow regulation. Methods:As detected by NanoString nCounter miRNA Expression panel for 3xTg-AD mice, 61 cerebrovascular miRNAs and respective mRNA targets were examined using Ingenuity Pathway Analysis for canonical Cardiovascular (Cardio) and Nervous System (Neuro) Signaling. Results:The number of targets regulated per miRNA were 21±2 and 33±3 for the Cardio and Neuro pathways respectively, whereby 14±2 targets overlap among pathways. Endothelial miRNAs primarily target members of the PDE, PDGF, SMAD, and VEGF families. Individual candidates regulated by≥4 miRNAs that best mark AD pathology presence in 3xTg-AD mice include CFL2, GRIN2B, PDGFB, SLC6A1, SMAD3, SYT3, and TNFRSF11B. Conclusion:miRNAs selective for regulation of endothelial function and respective downstream mRNA targets support a molecular basis for dysregulated cerebral blood flow regulation coupled with enhanced cell growth, proliferation, and inflammation.
