The role of APOE and Bone Morphogenic protein 4 (BMP4) in early cellular pathophysiology of Alzheimer's Disease

APOE 和骨形态发生蛋白 4 (BMP4) 在阿尔茨海默病早期细胞病理生理学中的作用

基本信息

  • 批准号:
    10710173
  • 负责人:
  • 金额:
    $ 4.77万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2022
  • 资助国家:
    美国
  • 起止时间:
    2022-09-01 至 2024-08-31
  • 项目状态:
    已结题

项目摘要

Project Summary Alzheimer’s disease (AD) is a heterogeneous neurodegenerative disorder categorized clinically by premature deficits in learning and memory that gradually progress to severe dementia. Although familial forms of the disease are caused by mutations in specific genes, the majority of AD occurs sporadically (sAD). The strongest risk factor for sAD diagnosis is age, implicating biochemical changes that occur across lifespan that increase pathogenic susceptibility. One of the changes that occur throughout aging in both human and rodent brains is an increase in BMP4 signaling, in a manner that is significantly negatively correlated with cognitive decline and decreased spatial memory in mouse models. The strongest genetic risk factor for sporadic Alzheimer’s disease is apolipoprotein E (APOE) genotype; the APOEε4 isoform is significantly more prevalent in AD populations and has been linked to increased disease progression and earlier age of onset. Previous work in the Kessler lab has shown that APOEε4 neurons, compared to APOEε3 isogenic control neurons, express increased levels of phosphorylated tau and have greater predisposition to cell death in response to external stressors such as ionomycin. The current proposal seeks to understand the interaction between increased BMP4 and APOEε4 expression at the cellular level to understand early sAD disease pathogenesis. To answer this question, our laboratory has generated induced pluripotent stem cells (iPSCs) from patients with sporadic AD and used CRISPR-/Cas9 editing of APOEε3/4 cells to create isogenic APOEε3/3 lines. These cells are then differentiated into neurons and astrocytes to determine cell-autonomous and non-cell autonomous cellular pathology involved in increased BMP4 signaling and APOEε4 expression. The first aim will test the hypothesis that increased BMP4 in tandem with APOEε4 expression elicit additive effects that negatively alters astrocytic expression and homeostatic functions. To test this hypothesis, transcriptomics will be used to determine differential gene expression and subsequent studies will be used to address protein expression and functional changes may occur. The second aim will utilize iPSC patient-derived cocultures of neurons and astrocytes in matched or mismatched isogenic pairs to determine non-cell autonomous changes that occur as a result of increased BMP4 signaling and APOEε4 genotype, testing the hypothesis that APOEε4 astrocytes, along with increased BMP4 signaling, exaggerate pathological cascades in neurons, leading to decreased viability subsequent cell death of neurons. The purpose of the first aim is to determine how astrocytes, whose trophic support is necessary for neuronal viability, alter homeostatic functions in response to sAD risk factors. The second aim will uncover how these cell-autonomous changes in astrocytes ultimately modify early disease pathology in neurons. The overall long-term goal is to identify early targetable mechanisms for successful intervention in this devastating disease.
项目总结

项目成果

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Anne Kathryn Linden其他文献

Anne Kathryn Linden的其他文献

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{{ truncateString('Anne Kathryn Linden', 18)}}的其他基金

The role of APOE and Bone Morphogenic protein 4 (BMP4) in early cellular pathophysiology of Alzheimer's Disease
APOE 和骨形态发生蛋白 4 (BMP4) 在阿尔茨海默病早期细胞病理生理学中的作用
  • 批准号:
    10535543
  • 财政年份:
    2022
  • 资助金额:
    $ 4.77万
  • 项目类别:

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