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.