Effects Of Chronic Heart Failure And Transgenic Parkin On Cognitive, Neuropsychological Behavior And Abeta Metabolism In Mice

I. Chronic heart failure mildly increases the risk of cognitive impairment and alters the metabolism of beta-AmyloidChronic heart failure (CHF) is a global epidemics incurring significant morbidity and mortality in ageing subjects. It is commonly associated with other chronic conditions e.g. coronary heart disease (CHD), chronic obstructive pulmonary disease (COPD), cardiacarrhythmia and diabetes. The prevalence of heart failure increases with the age and now chronic heart failure remains a major public health problem.Alzheimer disease (AD) is a neurodegenerative disorder in the central nervous system (CNS), clinically characterized by progressive loss of memory and other cognitive skills resulting in severe dementia. The neuropathological hallmarks of AD are the presence in the brain of extracellular senile plaques and intracellular neurofibrillary tangles, along with neuronal loss. Behavioral and psychological symptoms of dementia (BPSD) such as disturbances in mood, emotion, appetite agitation, and depression are non-cognitive symptoms commonly associated to AD.Heart failure, a multisystem disorder, affects not only the cardiovascular system but many other body organs and functions. Cardiac disease (CD) and AD share many pathological mechanisms. And researches from epidemiology and clinico-pathology show CD may be causal in the progress of AD. They also share some similarities such as hypoperfusion and inflammation.In this study, we illuminate the cognition and BPSD influenced by CHF and the possible mechanism. Myocardial infarction (MI)/congestive heart failure (CHF) model was adopted to mimic the pathological progress in human beings. Adult male or female mice (10～12week old) received heart surgery---occlusion of the left anterior descending coronary artery. High-frequency echocardiography was performed to exam the cardiac functions. Both male and female mice with chronic heart failure displayed mildly impairment of learning in the task of Morris Water Maze. Open field test, elevated plus maze test, tail suspension test, novel object recognition test were also performed. The metabolism of β-amyloid was altered in female mice, while the male mice were quite normal in the metabolic pathway of β-amyloid.Our findings give a clear connection that chronic heart failure mildly increases the risk of cognitive impairment, hyperanxious and alters the metabolism of β-amyloid especially in female mice. What we found indicates that chronic heart failure is a risk factor for Alzheimer’s disease. II. Parkin promotes cerebral beta-amyoid clearance and improves the behaviors in APP/PS1miceMore and more people were suffered from neurodegenerative diseases as the population continue to age. These diseases are an ever-increasing socioeconomically costing and become the priority of health concern.Alzheimer disease (AD) is the most common type of dementia in clinical surveys, which is caused by progressive neuronal loss throughout the brain. Its neuropathological hallmarks include extracellular senile plaques (SPs) and intracellular neurofibrillary tangles (NFTs). At present, there is no quite effective treatment for Alzheimer disease.The ubiquitin-proteasome system (UPS) pathway is involved in the degradation of numerous proteins and it’s regarded as an important mechanism in regulation of many physiological events of cells. E3ubiqituin ligases, which act as substrate-specific regulators and are involved in a series of cellular processes, play a core role in the UPS system. Recent years, many progresses on UPS and ubiquitin ligases, have been achieved in the nervous system.The functions of ubiquitin modification and ubiquitin-proteasome system have been extensively investigated in AD. The ubiquitin-positive protein aggregates are presented in the senile plaques and NFTs.In this study, we analyzed the expression of several UPS genes in mouse brain during aging by real-time PCR, and found a wide range of alterations. The UPS may play crucial roles in brain development and senescence. Deficiency of UPS may cause neurodegenerative disorders, such as AD. E31igase UCHL-1, Cbl, Cbl-b and Parkin were further studied due to their significant transcriptional changes and being related to cognition. Stable cell lines with overexpressed or downregulated UCHL-1, Cbl, Cbl-b or Parkin were constructed base on AD cellular model (APPsw-SY-SH5Y). The work concerning E3ligases and cell aging is still going on.Parkin participates in beta-amyoid clearance. To know the in vivo functions of Parkin in AD and the mechanisms, APP/PS1mice were crossed with Parkin transgenic mice, and APP/PS1/Parkin triple transgenic mice were generated. Behavior tests, including Open Field test, Elevated Plus Maze test, Tail Suspension test and Morris Water Maze test, were conducted. Overexpression of Parkin could significantly improve the cognitive behavior and behavioral and psychological symptoms of dementia (BPSD) in APP/PS1mice. Furthermore, Parkin could reduce APP expression and its metabolic downstream products---CTFs, promote beta-amyoid clearance, and concomitantly reverse the LTP impairment in APP/PS1mice.