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

探索Na泵抑制剂marinobufagenin在认知障碍和阿尔茨海默病中与年龄相关的血管和神经退行性过程之间的相互作用中的作用

• 批准号: 10259332
• 负责人: Olga V Fedorova
• 金额: $ 256.53万
• 依托单位: NATIONAL INSTITUTE ON AGING
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10259332
• 关键词: APP-PS1; ATPase inhibitory protein; Affect; Age; Age-Months; Aging; Alzheimer' s Disease; Amyloid; Amyloid Beta A4 Precursor Protein; Amyloidosis; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animal Model; Animals; Antihypertensive Agents; Anxiety; Aorta; Attention; Auditory; Blood Vessels; Brain; Cardiovascular Diseases; Cardiovascular Pathology; Cardiovascular system; Cells; Cerebrovascular Circulation; Cerebrovascular system; Control Animal; Core-Binding Factor; Dahl Hypertensive Rats; Data; Databases; Dementia; Development; Diet; Elderly; Exhibits; Genes; Heart; Hippocampus (Brain); Histocytochemistry; Human; Hypertension; Impaired cognition; Impairment; Implant; Impulsivity; Inflammatory; Intervention; Learning; Light; Lisinopril; MRI Scans; Magnetic Resonance Imaging; Memory; Microscopy; Microvascular Dysfunction; Modeling; Mus; Na(+)-K(+)-Exchanging ATPase; Nerve Degeneration; Neurons; Pathology; Performance; Perfusion; Pharmacology; Physiologic pulse; Prevention; Process; Production; Rattus; Risk Factors; Senile Plaques; Serum; Smooth Muscle Myocytes; Sodium Chloride; Steroids; Structure; Synaptic plasticity; Testing; Time; Transgenic Mice; Translating; Travel; Urine; Vascular Dementia; Vascular Smooth Muscle; Vascular blood supply; Visual; Water; Wild Type Mouse; age related; arm; arterial stiffness; behavior test; beta amyloid pathology; cerebral artery; cognitive function; cognitive performance; density; distraction; experimental study; hemodynamics; improved; inflammatory marker; inhibitor/antagonist; male; marinobufagenin; morris water maze; mutant; novel; overexpression; predictive marker; premature; rate of change; salt intake; spatial memory; subcutaneous; therapeutic target; trend; trial comparing; wasting; water maze

Experiment 1. 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. This study is in progress; after the finalizing of the database analyses, the linear mixed effect model analysis will be performed. Experiment 2. 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 plaques and exhibit impaired learning development with an advancing age and are widely used to study AD and AD-related pathologies. APP/PS1 double mutant transgenic mice with overexpressed human AD genes, were used in our study. We demonstrated that AD mice have lower level of Na/K-ATPase inhibitor marinobufagenin (MBG) vs. non-transgenic wild type (WT) control mice even in the presence of cardiovascular pathologies, i.e., higher pulse wave velocity (PWV) 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 APP production. Next, 12 months old male AD and WT mice were implanted subcutaneously Alzet minipumps for the continuous MBG delivery for 2 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 2 months 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 14 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 A 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 which can promote the further plaque formation. Notably, that the cardiovascular amyloidosis was detected in aorta and heart of AD mice vs. WT, which can explain the central cardiovascular pathology observed in 2xTg-AD mice.