DEVELOPMENT OF AN ACCELERATED ALZHEIMER’S DISEASE IN VITRO MODEL WITH THE ADDITION OF PROGERIN

Abstract

Alzheimer’s Disease (AD) is one of the most common causes of dementia. Twopathological features of AD include amyloid plaques and neurofibrillary tangles. The mechanism underlying the disease's onset and progression remains unclear. Lamin A is an essential component of the nuclear lamina, and nuclear lamina plays a vital role in essential cell functions. Specific mutations in lamin A yield a truncated protein called progerin that causes Hutchinson-Gilford Progeria Syndrome (HGPS), a premature aging disease. Despite the low expression of lamin A in the brain, several studies reported abnormal lamin A accumulation in patients' hippocampus through the different stages of AD. Besides, there are a lot of common phenotypes between AD and HGPS. Meanwhile, one of the challenges of studying AD is the model issue. It is difficult to recapitulate all AD pathology in a single model, and most models are time-consuming. This dissertation focuses on goals: (1) exploring the potential role of lamin A in AD and (2) facilitating the AD model development. To investigate the potential role of lamin A in AD, I overexpressed either lamin A or progerin in neural cells and checked the phenotypes in Chapter II. Early cell death is closely associated with neuronal loss in AD. After ectopically expressing lamin A in neural cells, early cell death was slightly increased. Progerin could worsen these phenotypes. Oxidative stress and cell cycle re-entry are early events in neurodegeneration and are associated with increased cell death. With the ectopic expression of lamin A, neural cells exhibited slightly elevated oxidative stress and significantly increased cell cycle reactivation. Both two events were significantly increased with exogenous progerin. These results provide insights into how lamin A is involved in neurodegeneration. Besides, progerin addition could further disrupt cellular homeostasis and therefore provide a potential environment for modeling late-onset disease. Most of the current cellular models for AD require several months to display AD phenotypic features, mainly because of the lack of an aging environment in the in vitro cell culture, which is an essential player in age-related neurodegeneration. To provide the aging environment for modeling AD, I examined the impacts of exogenous progerin expression on the neural progenitor cells carrying familial AD mutations (FAD) in Chapter III. Exogenous progerin could accelerate hallmark AD phenotype exhibition from 8-16 weeks to 3-4 weeks, including increased tau phosphorylation and Aβ42/Aβ40 ratio in 2D cell culture, and accumulation of amyloid plaques in 3D cell culture. Additional AD cellular phenotypes, including elevated cell death and cell cycle re-entry, were significantly increased after progerin intervention as well. Together, these results indicated that the approach with progerin expression could create an accelerated model for modeling AD development and future drug screening.