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Molecular signaling linking Alzheimer's disease and heart failure

阿尔茨海默病和心力衰竭之间的分子信号传导

基本信息

批准号：
10287798
负责人：
Md. Shenuarin Bhuiyan
金额：
$ 36.5万
依托单位：
LOUISIANA STATE UNIV HSC SHREVEPORT
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-12-15 至 2023-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10287798
关键词：
Accounting Adrenergic Agents Age-Years Agonist Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease pathology Alzheimer&apos s disease patient Alzheimer&apos s disease risk Amyloid Amyloid beta-42 Amyloid beta-Protein Amyloid beta-Protein Precursor Amyloid deposition Architecture Autopsy Binding Sites Biochemical Brain Calcium Cardiac Cardiac Myocytes Cardiovascular Diseases Cessation of life Clinical Research Dementia Deposition Development Disease Energy Metabolism Etiology Exhibits Functional disorder Generations Genetic Genetic Polymorphism Goals Heart Heart failure Homeostasis Human Human Amyloid Precursor Protein Impaired cognition Impairment In Vitro Knockout Mice Link Mediating Memory Loss Metabolic Metabolic dysfunction Metabolic stress Metabolism Mitochondria Modeling Molecular Molecular Genetics Molecular Target Morphology Mus Mutation Myocardial Myocardial dysfunction Myocardium Neurodegenerative Disorders Parents Pathogenesis Pathogenicity Pathologic Pathology Pathway interactions Patients Pharmacology Physiological Plant Roots Presenile Alzheimer Dementia Reactive Oxygen Species Receptor Activation Reporting Research Respiration Risk Role Sampling Senile Plaques Signal Transduction Stress Structure Testing Transgenic Mice Transgenic Organisms abeta accumulation age related cell injury cognitive function density extracellular genetic regulatory protein in vivo interest lipid metabolism loss of function mitochondrial dysfunction mitochondrial metabolism mouse model mutant nervous system disorder new therapeutic target novel older patient overexpression presenilin-1 pressure prevent receptor receptor expression receptor function restoration sigma-1 receptor tau Proteins tau-1 therapeutic target

项目摘要

Project Summary: Alzheimer’s disease (AD) and heart failure (HF) are age-dependent diseases causing a substantial death in older patients. Pronounced cardiac pathology and dysfunction has also been reported in AD patients and different mouse model of AD. Despite extensive studies, the relationship between HF and AD remains largely unclear. We became interested in uncovering the molecular function of Sigma-1 receptor (Sigmar1) proteins in AD as studies showed that: i) Sigmar1 binding sites are reduced in postmortem samples from patients with AD, ii) the density of Sigmar1 is reduced in early AD, and iii) polymorphisms in Sigmar1 have been associated with altered risk for AD. We found that Sigmar1 is abundantly expressed in the body and Sigmar1 global knockout mouse heart showed impaired mitochondrial respiration suggesting a potential function of Sigmar1 in cellular metabolism. In the parent proposal, we wanted to test the central hypothesis that Sigmar1-dependent activation of metabolism is protective against metabolic stress-induced cardiac dysfunction and pathological remodeling. To determine, the molecular function of Sigmar1 in AD pathogenesis, we will use the APPswe/PS1 double transgenic mice expressing a chimeric mouse/human amyloid precursor protein (Mo/HuAPP695swe) and a mutant human presenilin 1 (PS1-dE9). The APPswe/PS1 mouse model having AD pathology, including accumulation of Aβ and phosphorylated tau proteins, as well as cognitive impairment and also develop cardiomyocyte contractile dysfunction. Here, we will test the central hypothesis that sustained Sigmar1 expression in the APPswe/PS1mouse model of AD will decrease the Aβ accumulation and cellular injury in the brain and heart through activation of mitochondrial energy metabolism. In this present Alzheimer’s supplement proposal, we will determine the role of Sigmar1 in Aβ accumulation, cognitive dysfunction and cardiac dysfunction in APPswe/PS1 mouse model of AD (Aim 1) and determine if sustained Sigmar1 dependent restoration of mitochondrial energy metabolism and function rescue AD pathogenesis and cardiac dysfunction APP/PS1 mouse (Aim 2). We will use integrated molecular, genetic, and functional approaches in conjunction with genetically modified mice to determine the direct involvement and define the molecular mechanisms of Sigmar1’s role in AD pathogenesis. This proposed project will identify a novel therapeutic target in protecting against APPswe/PS1-induced metabolic alterations, mitochondrial dysfunction, cellular injury, and adverse pathological remodeling.