Marinobufagenin as a therapeutic target

National Institute On Aging

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Abstract

Experiment 1. APP/PS1 double mutant transgenic mice with overexpressed human AD genes (2xTg-AD; AD mice), exhibit early cognitive impairment and amyloid-beta pathology as well as changes in hippocampal synaptic plasticity associated with AD development. These mice develop amyloid-beta plaques and exhibit impaired learning development with an advancing age and are widely used to study AD and AD-related pathologies. The AD mice and non-transgenic wild type (WT) control were used in our study. We demonstrated that AD mice have lower level of Na/K-ATPase inhibitor marinobufagenin (MBG) vs. WT control mice even in the presence of cardiovascular pathologies, i.e., higher pulse wave velocity and heart remodeling, which may be due to the amyloid accumulation. Notably, that MBG down-regulated APP gene in the cultured vascular smooth muscle cells. We hypothesized that MBG treatment may improve cognitive performance in AD mice via affecting the amyloid precursor protein (APP) production. The old male AD (12-14 months old) and age-matched WT mice were implanted subcutaneously Alzet minipumps for the continuous MBG delivery for 3 months. T-water maze reversed learning, O-maze behavioral tests and the brain histochemistry were performed at the end of the study. We observed moderate spatial memory improvement after 12 weeks of MBG administration. AD mice treated with MBG demonstrated lower number of turn errors in reversed trials compared to vehicle-treated AD mice. Number of trials in reversal task was normalized on number learning trials to select the correct arm with a platform in a T-maze. The AD mice at the end of the study at 15-17 months of age exhibited tendency of the higher anxiety level by spending less time in the open spaces vs. age-matched WT mice in O-maze test. Old AD mice were also numerically less active and moved slower compared to the WT mice. Notably, that AD and WT mice exhibited opposite trends in the O-maze activity after MBG treatment, i.e., WT mice become numerically more active and AD mice become numerically less active after MBG administration vs. vehicle administration. In addition, we demonstrated that most of the amyloid-beta plaques in the brains from old AD mice localized close or around the small cerebral blood vessels, which may reduce the ability of the cerebral circulation remove the cell metabolites, waste and debris, and promote the further plaque formation. Notably, that the cardiovascular amyloidosis was detected in aorta and heart of AD mice vs. WT mice, which can explain the central cardiovascular pathology observed in AD mice. Experiment 2. The postmortem human brain tissue samples used in this study were obtained from the Human Brain Collection Core (HBCC), Intramural Research Program, Bethesda, MD, USA. Twenty brain samples from the patients with bipolar disorder (BP) and 20 control subjects were received. The samples were tested for the MBG concentration and Na/K-ATPase abundance. The Na/K-ATPase alpha-2 and alpha-3 isoforms were significantly higher in the prefrontal cortex of BD patients compared with those in the controls. No difference in Na/K-ATPase alpha-1 isoform abundance between the two groups was detected. Significantly lower levels of brain MBG were detected in BD patients as compared with those in the controls. These findings support previously published observations, that Na/K-ATPase-CTS/MBG system is involved in neurodegenerative diseases development. The oxidative stress and inflammation, which are also involved in the Na/K-ATPase-MBG interaction, may add to the compromised brain biochemistry and support the vicious circle of depression and/or development of cognitive impairment. We also suggest that the levels of ECS are changed in the mania stage, which may cause the compromised interaction of ECS and Na+, K+-ATPase. The estimation of CTS levels in the plasma or cerebrospinal fluid of BD patients may provide an additional mechanistic basis for the proposed mechanisms involved in the development and progression of BD.