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

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The Dahl-S rat animal model exhibits premature central and cerebral vascular remodeling, associated with premature cognitive decline. Increased CAS in this model, indexed as pulse wave velocity (PWV), is mediated by activation of arterial wall pro-fibrotic pathways that are similar to those observed in human aging, and result in increased MBG levels (Fedorova et al. Circulation 2000 and 2002; Fedorova et al. Hypertension 2001) and increased arterial wall collagen deposition. Dahl-S rats were selected, by backcrossing, for the trait of salt-sensitivity of blood pressure. A major abnormality in Dahl-S rats is the development of renal and cardiovascular tissue fibrosis even on a low salt diet. Angiotensin II (ANGII) signaling participates in production of MBG which becomes increased in Dahl-S rats with advancing age. Both ANGII and MBG are implicated in pro-fibrotic signaling and central arterial stiffness increase. Because of that Dahl-S is an excellent model to study arterial fibrosis resulting in increased CAS and microvascular disease. Life span was measured in 60 S-D and 78 Dahl-S. Systolic BP (SBP), pulse wave velocity (PWV), plasma angiotensin II (ANGII), MBG and aortic collagen abundance were assessed in 3 and 9-mo males S-D and Dahl-S on a normal 0.5% NaCl intake (8 animals per group). Behavioral Morris water maze test was performed in 3 and 12 months old S-D and DSS. MRI scans taken with a 7 Tesla 30 cm Biospec, were obtained in S-D and Dahl-S at 3 and 6 months (8 animals per group). Brain regions were segmented using VivoQuant and their volumes were normalized to the whole brain. We have demonstrated that median life span in Dahl-S is reduced by 50% in comparison to S-D (12+/-1 months vs. 24+/-2 months, p<0.01). At 3 months old DSS had higher SBP (143+/-2 mmHg vs. 128+/-2 mmHg, p<0.05), PWV (4.2+/-0.8 m/s vs. 2.4+/-0.1 m/s, p<0.05), plasma ANGII (43.8+/-1.4 pg/ml vs. 19.8+/-1.6 pg/ml, p<0.05), urine MBG (62+/-2 vs. 38+/-4 pmol/24 hr/kg BW, p<0.05), increased aortic (by 80%, p<0.05) and large cerebral (by 60%, p<0.05) arterial wall collagen abundance vs. 3 month old S-D. Between 3 and 9 months Dahl-S, but not S-D, exhibited further increase in SBP (by 38 mmHg, p<0.05), PWV (1.5-fold, p<0.05), MBG (by 60%, p<0.05) and aortic collagen deposition (by 40%, p<0.05). In a redundant place-cue version of the Morris water maze test, 3 months old Dahl-S demonstrated numerically impaired spatial hippocampal memory vs. 3 months old S-D, and by 12 months, performance in Dahl-S suggested the development of decline in hippocampal spatial memory component in comparison to age-matched S-D. Twelve months old Dahl-S traveled longer distance (9.3+/-0.9 m vs. 4.5+/-0.3 m, P<0.05) to find a hidden platform than 12 months old S-D. In linear regression analysis increased SBP (166+/-15 mmHg), accompanied by advanced age, was associated with larger amygdala (R-squared =0.90, p<0.05) and hippocampal (R-squared =0.97, p<0.05) volumes. Cortex volume was higher in Dahl-S than S-D at a SBP of 156+/-5 mmHg (R-squared =0.80, p<0.05). At 3 months, the total concentration of a brain metabolite N-acetylaspartate (NAA; a measure of neuronal density) was higher in S-D compared to age matched DSS in the pre-frontal cortex (6.25 +/- 0.66 vs. 5.13 +/- 0.46, p<0.05) and hippocampus (5.7+/-0.4 mM vs. 4.5 +/- 0.5 mM, respectively, p<0.05). The ratio of NAA:total creatine in these brain regions did not differ significantly in Dahl-S versus S-D (p>0.05). At 6 months, Dahl-S had a significantly higher T2 (a measure of tissue relaxivity) in the hippocampus (54.9+/-1.3 ms vs. 51.7+/-0.94 ms, p<0.001) and amygdala (54.9+/-1.5 ms vs. 52.0+/-0.90 ms, p<0.001) compared to S-D. These finding indicate that in Dahl-S high MBG occurred concurrently with fibrosis of aorta and large cerebral arteries and numerically impaired spatial memory. With advancing age of DSS further increase in BP, aortic stiffness and spatial learning/memory deficit occurred in context with an increase in MBG, which suggested an implication of MBG in these declines. The hippocampus, amygdala and cortex structural changes are modulated by age-dependent hypertension and are associated with age-related modifications in brain tissue volume, neuronal decline and decreased tissue relaxivity in Dahl-S rats. Thus, Dahl-S rats represent a suitable model to study the development of cognitive impairment and dementia due to the changes in cerebral microvasculature and central arterial wall, which underlie by changes in the status of pro-inflammatory and pro-fibrotic factors.