Alzheimer?s disease (AD) is the most common neurodegenerative disorder in humans. Despite several decades of intense research there are currently still no effective treatments for AD. There has been considerable interest in exploring the use of induced pluripotent stem cells (iPSCs) as a novel tool to study AD, as the technology can capture the precise genetic background of a given AD patient. Furthermore, it is now possible to generate large numbers of such patient-specific, human iPSC-derived neurons on demand. This represents a powerful tool to study AD disease mechanisms in vitro, and to develop and test novel candidate therapies using iPSC-based screening assays. However, a problem that has plagued the iPSC field is the immature, fetal-like nature of the resulting neurons that does not match the age-related characteristics of AD patients. Furthermore, any age- related cellular markers that are present in primary cells from AD patients appear to be rejuvenated after reprogramming back to pluripotency. To address those limitations, we have recently reported on strategies to artificially trigger age-related marker expression in iPSC-derived neurons by manipulating pathways known to cause premature aging. Furthermore, we have provided proof-of-concept for using such induced aging strategies in iPSC models of Parkinson?s disease. Those ?induced aging? strategies include the ectopic expression of progerin, a mutant form of the nuclear lamina protein LMNA, and the shortening of telomeres prior to and during neural differentiation. Additional candidate strategies reported by other labs include knockdown of the RanBP17 gene, a factor involved in nuclear/cytoplasmic transport and global loss of heterochromatin, an epigenetic cellular change that triggers premature aging-like feature in fibroblast. The goal of the current study is to test current and to develop novel induced aging strategies that may be particularly suitable to model AD. First, we aim to compare several current induced aging strategies in AD-iPSC-derived cortical neurons to assess, side-by-side, their ability to trigger age-related marker expression and AD-related biochemical and degenerative changes. To model the AD-specific effects, we will use isogenic AD-iPSC lines, recently established, carrying mutations in APP(Swe) and presenilin 1 (PSEN1(M146V). Second, we will identify and validate novel candidate induced aging strategies of particular relevance in triggering degenerative phenotypes in AD- but not in control iPSC-derived neurons. Third, we will use the most promising strategies from Aim 1 and Aim 2 to determine their ability to trigger disease phenotypes in iPSC-derived cortical neurons derived from patients with sporadic AD. Sporadic AD patients represent the most common form of the disease and have been particularly difficult to model using conventional iPSC technology. The proposed study will address whether current or novel induced aging strategies can contribute to improved iPSC models of AD. Similar approaches may apply to many other late-onset disorders and could offer fundamental insights into the mechanism of neuronal aging.
The study of Alzheimer?s disease (AD) using patient-specific cells is complicated by the fact that iPSC-derived neurons exhibit rejuvenated, embryonic-like properties. We have previously developed strategies to artificially induce age-like features in iPSC-derived neurons by expressing genes that cause premature aging. The goal of the current study is to use such technology in models of AD. We will define whether induced aging can trigger age- and disease related features in AD-iPSC cortical neurons and whether it can trigger robust disease phenotypes not only in familial but also in sporadic cases of AD.