Alzheimer?s Disease (AD) is the most common neurodegenerative disease in the United States affecting an estimated 5.4 million patients48. To date, there are no effective cures and limited therapies available for patients49. 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 understood50. 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 donor51. Studies have shown the process of iPSC reprogramming resets the age of patient iPSCs5. Consequently, cells derived from iPSCs tend to yield immature and prenatal cell types, presenting a major hurdle for late-onset disease modelling5, 6. Induced aging protocols are a novel strategy for accelerating age in iPSC-derived cells for modelling late-stage degenerative disease phenotypes5,6. 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 proteins8-10, 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.
This study will establish an hPSC-derived model of Alzheimer?s Disease for drug screening and disease modelling purposes. The proposed experiments will elucidate any causal relationship or potential crosstalk between age-associated decline in nuclear lamina and transport activity, potentially identifying a master regulator of nuclear and cellular aging. The induced aging strategies outlined in this proposal could further be applied to non-neuronal cell types for modelling late-onset diseases of other lineages.
