Exploring the association of Na pump ligands with vascular dysfunction and neurodegeneration in Alzheimer's disease and related dementias

National Institute On Aging

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Abstract

To reach the Aims of this study we performed the following experiment. Sixteen double-mutant 2x-Tg-AD (APPswe/PS1dE9; 2xTg-AD; AD) male mice and 8 wild type (WT) male mice (15-mo old) were included in the experiment. Eight AD mice and 4 WT mice were administered MBG (AD-MBG and WT-MBG groups) or vehicle treatment (control groups: AD-C, n=8; WT-C, n=4). MBG (100 microgram/day/kg body weight) was administered using sub-cutaneous ALZET osmotic minipumps over the course of 12 weeks. Systolic blood pressure (SBP; by tail cuff plethysmography), and open field test (OFT) results were collected before and after treatment at 15-mo and 18-mo correspondently. Tissue and plasma samples were collected after the treatment for further analysis. Plasma MBG was measured by immunoassay, mRNA expression was estimated by qPCR in brain samples. Data were analyzed by 2-way ANOVA and t-test and presented as average ± standard error. We demonstrated that WT-C and AD-C mice had similar SBP and body weight; MBG treatment did not affect these parameters in WT-MBG and AD-MBG. Plasma MBG was lower in AD-C mice vs. WT-C (0.13 ± 0.02 nmol/L vs. 0.22 ± 0.04 nmol/L, correspondently; P<0.05 by t-test). MBG treatment was associated with higher plasma levels of MBG in both WT-MBG and AD-MBG mice (0.48 ± 0.12 nmol/L vs. 0.66 ± 0.18 nmol/L, correspondently). AD-C mice had 1.6-fold higher brain expression of inflammatory marker interleukin-6 (IL6) mRNA vs. WT-C; MBG treatment significantly reduced mRNA IL6 expression in AD-MBG mice vs. non-treated AD-C mice. No differences were found for total traveled distance, nor for time spent in the center during the first 90 seconds of the OFT between AD-C and WT-C, and between AD-MBG and AD-C. We demonstrated a significant effect of strain (p<0.05), a significant effect of MBG treatment (p<0.05), and a borderline effect of interaction of treatment with strain (p<0.1) for the distance traveled in the center during the first 90 seconds (by 2-way ANOVA). WT-C mice traveled farther distances in the center of the open field compared to AD-C mice. Mice treated with MBG traveled less in the center than non-treated mice. Treatment did not affect the distance traveled in the center for AD mice; whereas, WT-MBG mice traveled less in the center of the field compared to WT-C. In conclusion, the old non-treated AD mice had lower plasma MBG and higher brain inflammatory marker IL6 vs. non-treated WT mice. Although MBG treatment did not affect behavioral test results in the AD mice, it significantly reduced the level of pro-inflammatory marker IL6 mRNA in brain. Future directions: whether the treatment with MBG, initiated at earlier age, will demonstrate more therapeutic and cognitive benefit in the mouse AD model remains to be determined. The mechanism of anti-inflammation effect of NKA ligand MBG will be investigated in the cell cultures of brain cells.