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

Experiment 1. Dahl-S rat model of age-associated vascular dementia Central arterial stiffness (CAS) is associated with elevated arterial blood pressure (BP) and is likely associated with stiffening of cerebral artery walls, with attendant cerebral hypoperfusion, neuronal density loss and cognitive decline. Dahl salt-sensitive (Dahl-S) rats exhibit age-associated hypertension and memory loss, even on a normal salt intake. We sought to explore whether central arterial pulse wave velocity (PWV), a marker of CAS, is associated with hippocampal cerebral blood flow (CBF) and neuronal density in hypertensive Dahl-S rats. We measured systolic BP (by tail-cuff plethysmography), aortic PWV (by echocardiography) and CBF and N-acetyl aspartate (NAA) (by magnetic resonance imaging) in twelve 6 months old male Dahl-S rats. We have demonstrated that greater PWV was significantly associated with lower CBF and lower NAA concentration in the hippocampus, supporting a role of CAS in cerebrovascular dysfunction and decline in cognitive performance with aging. These findings implicate increased CAS in cerebral hypoperfusion and loss of neuronal density and function in the Dahl-S model of age-associated cardiovascular dysfunction. Experiment 2. Effect of an ACE inhibitor in the Dahl-S rat model of age-associated vascular dementia A premature increase in aortic stiffening and BP, accompanied by spatial cognitive impairment, occur in Dahl salt-sensitive rats (Dahl-S) on a normal salt intake with advancing age. Because a novel pro-hypertensive and pro-fibrotic steroid, marinobufagenin (MBG), is implicated in BP increases in Dahl-S, we hypothesized that the changes in the levels of the pro-fibrotic factors, including MBG and angiotensin II, which stimulates MBG, will cause the arterial wall stiffening, which will lead to the structural changes in the cerebral arteries and neurons following by cognitive decline. We posited that pharmacologic interventions targeting age-dependent pro-fibrotic processes within the arterial wall to reduce central arterial stiffness, will ameliorate brain microvascular disease, cognitive impairment and dementia. Dahl-S (n=20) male rats were fed a normal salt diet for 12 months; 10 of them were continuously treated with an ACE inhibitor Lisinopril (15 mg/kg/day) administered through their water for 6 months, and 10 Dahl-S rats remained on regular water as a control (2 non-treated control animals died before the end of the experiment due to hypertension). Systolic BP (SBP), PWV, urine MBG, brain MRI scans, open field and attention tests (Fig. 1) were performed at 6 (baseline), 9 and 12 months, while Morris water maze (MWM) test and brain histochemistry were performed at 12-mo. We demonstrated that (i) greater PWV, a marker for CAS, was associated with a decreased hippocampal perfusion and a decreased neuronal mass (NAA). Higher hippocampal perfusion was associates with the lower anxiety level. This finding suggests that central arterial stiffness may be a potential therapeutic target for the prevention and treatment of dementia. (ii) Next, we demonstrated that Lisinopril treatment was associated with a decrease in PWV and SBP, and that MBG level was stable for the duration of the study in the treated rats whereas control animals exhibited increase in MBG and higher SBP and PWV. (iii) In hypertensive Dahl-S rats, Lisinopril treatment improved spatial hippocampal memory, which was associated with a decrease of distance traveled to find a hidden platform in Morris water maze and with a better path efficiency vs. non-treated controls. (iv) Preliminary results in attention test suggest that Dahl-S rats treated with Lisinopril for 6 months demonstrated increased attention during a challenge with auditory and visual distractions (p=0.04). Further analysis will be done to assess impulsivity and compulsivity in this attention test. (v) In addition, we found, that Lisinopril-treated animals demonstrates stabilization of hippocampal CBF and NAA (brain MRI data) while untreated animals exhibited trend to decline of these values with aging. Increased performance for treated animals in MWM points to spatial hippocampal memory benefits of treatment that support trends seen for hippocampal CBF and NAA. These findings are consistent with the preliminary brain vessels density histochemical data, obtained by a green light sheet microscopy. Dahl-S rats treated with Lisinopril, exhibited an increase in blood vessel density vs. non-treated controls, which can be translated that a higher blood supply to the brain is resulted after anti-hypertensive and anti-fibrotic treatment.