Exploring the involvement of Na pump inhibitor marinobufagenin in the interactions between age-associated vascular and neurodegenerative processes in cognitive impairment and Alzheimer's disease

National Institute On Aging

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Abstract

The following experiment was performed to test the study hypotheses: We used male SD and DSS rats, which were kept on a normal salt diet (0.5% NaCl; n=8/group) for entire experiment. The longitudinal repeated and non-repeated measurements were performed at 3-mo and 12-mo of age. The following groups were used: DSS-3, DSS-12, SD-3 and SD-12. Repeated measurements (systolic blood pressure, SBP; pulse wave velocity, PWV, an index of CAS; echocardiography), and non-repeated measurements (Morris water maze, MWM, to test spatial memory; aortic collagen, elastin (estimated by histochemistry), and left ventricle (LV) mRNA expression (qPCR) of the genes related to fibrosis, inflammation and senescence) were assessed at 3-mo and 12-mo of age. Data analyses was performed using linear mixed-effect 2-way ANOVA, t-test and linear regression (LR) modeling. We have demonstrated, that SBP, PWV, aortic weight, wall thickness and collagen/elastin ratio were higher in young DSS-3 vs. SD-3. These parameters were also higher in DSS-12 vs. DSS-3, whereas only PWV and aortic wall thickness were higher in SD-12 vs. SD-3. Relative left ventricle wall thickness (RWT) and LV expression of pro-fibrotic genes (collagen1a2, 1.5-fold; TGFbeta1, 1.8-fold); inflammatory gene (TNFalpha1, 1.7-fold), and senescence genes (GDF15, 3-fold; TP53, 1.9-fold) were higher in DSS-12 vs. DSS-3 rats, and in DSS-12 vs. SD-12 rats. DSS-12 spent more time to find a hidden platform in MWM vs. SD-12 (47 +/-3 sec vs. 27 +/- 4 sec; p<0.05). Impaired spatial hippocampal memory in DSS-12 was positively associated with PWV and LV mass by LR analysis. Based on the results of this study we have concluded, that: (1) EVA, indexed as higher BP, PWV and aortic remodeling were associated with early CV aging, manifested by activation of LV senescence, inflammatory and pro-fibrotic genes and by higher rates of age-associated changes in BP, RWT and LV mass in DSS vs. SD. (2) In DSS, EVA and early CV aging was associated with memory decline later in life. (3) The DSS rat model exhibits close similarity to clinical vascular dementia by sharing the presence of hypertension and CAS, which precede cognitive decline development.