Define the effect of CLU SNP on the risk to Alzheimer's disease

项目总结

Project Summary Alzheimer’s disease (AD) is the most common form of dementia in the elderly and there is no cure for this disease. The molecular and cellular mechanisms underlying AD pathogenesis remains to be elucidated to develop effective therapies for this disease. Many mouse models have been generated for AD research and these models provide important insights to aid our understanding of the pathological basis of the disease. However, because there are significant species differences between mouse and human neural cells, establishing human disease modeling platforms is needed to complement studies in animal models to better understand AD. Human induced pluripotent stem cells (hiPSCs) have been widely used for disease modeling since the development of the iPSC technology. hiPSCs have been used to model various aspects of AD. Because hiPSCs and their derivatives have been considered phenotypically young, hiPSC-derived cells have been used to model early events of AD. Direct reprogramming is another type of reprogramming that converts one type of somatic cells into another without going through the iPSC stage that involves extensive epigenetic modifications, thus enabling generation of human cells that possess key elements of cellular aging. Therefore, directly reprogrammed cells derived from patient somatic cells would allow us to model age-related pathologies of AD. ApoE4 is the strongest and the C allele of the CLU rs11136000 SNP is the third strongest genetic risk factor for AD. The objective of this proposal is to define the effect of the CLU rs11136000 SNP alone or together with ApoE4 on the risk to AD and uncover molecular and cellular mechanisms underlying the effect, using human cellular models generated from hiPSCs or through direct reprogramming. We will use gene-edited isogenic cells to define the effect of CLU SNP in combination with ApoE isoform. In addition, because hiPSC-derived cells and directly reprogrammed cells derived from the same donors have the same genetic background but different cellular aging status, they represent isogenic cellular platforms that will enable us to specifically study the effect of cellular aging. These isogenic models will allow us to recapitulate age-associated phenotypes and uncover novel pathological mechanisms underlying AD. Because both CLU and ApoE are highly expressed in astrocytes, we propose to define the effect of the CLU SNP alone or together with ApoE using astrocytes. We hypothesize that CLU modulates AD pathologies in an ApoE isoform- and age-dependent manner. Therefore, we propose following Specific Aims: Aim 1: To derive astrocytes with different APOE/CLU genotypes and cellular aging status from hiPSCs or through direct reprogramming. Aim 2: To define the effect of APOE and CLU variants on AD pathogenesis using astrocyte-neuron or astrocyte-OPC co-cultures. Aim 3: To determine the relationship of APOE/CLU genotypes and aging with gene expression change in human brains. The proposed studies will help to define the roles of the CLU SNP in the development of age-associated AD pathologies, to uncover mechanisms underlying AD pathogenesis, and to design novel therapeutic strategies for AD.