Loss of nuclear integrity is sufficient to induce age-associated changes and Alzheimer's pathology in hPSC-derived cortical neurons.

项目简介:

Project Abstract: Alzheimer’s Disease (AD) is the most common neurodegenerative disease in the United States affecting an estimated 5.4 million patients 48. To date, there are no effective cures and limited therapies available for patients 49. While a small number of AD cases are linked to genetic mutations in Amyloid Precursor Protein processing, the genetic basis of most AD cases remains poorly understood 50. Induce Pluripotent Stem Cells (iPSCs) provide a unique opportunity to study the genetics of AD, by providing an unlimited supply of disease- relevant tissue while retaining the genetic background of their somatic cell donor 51. Studies have shown the process of iPSC reprogramming resets the age of patient iPSCs 5. Consequently, cells derived from iPSCs tend to yield immature and prenatal cell types, presenting a major hurdle for late-onset disease modelling 5, 6. Induced aging protocols are a novel strategy for accelerating age in iPSC-derived cells for modelling late-stage degenerative disease phenotypes 5,6. While these protocols have been established for generating iPSC-based models of Parkinson’s Disease, they have yet to be applied to AD. There are numerous studies which describe a decline in multiple aspects of nuclear homeostasis that occur with age and in AD patient brains, including differential expression of lamin proteins, a shift in nuclear-cytoplasmic transport activity, and a decline in nucleoporin and transport proteins 8-10, 22, 24, 25, 35-38. It is therefore plausible that a loss of nuclear integrity is sufficient to induce age-related and pathological changes associated with AD in hPSC-derived cortical neurons. The proposed research project aims to use genetic strategies to mimic age-associated changes within the nucleus to determine if nuclear perturbation is sufficient to drive other aspects of cellular age and potentiate AD pathology. These studies could create an innovative age-implicated model of AD, develop novel methods for modelling late-onset diseases in other cell types, and provide new insights into drivers of cellular and nuclear aging.