Development of an Accelerated Cellular Model for Alzheimer’s Disease

Alzheimer’s Disease (AD) is a leading cause of dementia characterized by amyloid plaques and neurofibrillary tangles, and its pathogenesis remains unclear. Current cellular models for AD often require several months to exhibit phenotypic features due to the lack of an aging environment in vitro. Lamin A is a key component of the nuclear lamina. And progerin, a truncated protein resulting from specific lamin A mutations, causes Hutchinson-Gilford Progeria Syndrome (HGPS), a disease that prematurely ages individuals. Studies have reported that lamin A expression is induced in the brains of AD patients, and overlapping cellular phenotypes have been observed between HGPS and AD cells. In this study, we investigated the effects of exogenous progerin expression on neural progenitor cells carrying familial AD mutations (FAD). Within three to four weeks of differentiation, these cells exhibited robust AD phenotypes, including increased tau phosphorylation, amyloid plaque accumulation, and an elevated Aβ42 to Aβ40 ratio. Additionally, progerin expression significantly increased AD cellular phenotypes such as cell death and cell cycle re-entry. Our results suggest that progerin expression could be used to create an accelerated model for AD development and drug screening. Significance Statement Alzheimer’s Disease (AD) contributes to most dementia, while its mechanism is still under investigation. One of the challenges for studying AD is the model issue, including the genetic divergence of animals and human, and the rejuvenation of induced pluripotent stem cells (iPSCs). Progerin is a mutant lamin A found in the accelerated aging disease progeria. There are a lot of molecular similarities between Alzheimer’s Disease (AD) and progeria. Here, we developed an accelerated 2D/3D cell model system for AD by ectopically expressing progerin in a previously characterized AD cell model carrying familial AD (FAD) mutations. Our study showed that progerin addition could accelerate AD phenotypical progression, including tau phosphorylation and formation of β-amyloid plaques. ### Competing Interest Statement The authors have declared no competing interest.