Exploring the Relationship Between Cellular Senescence, Apolipoprotein E, and Alzheimer’s Disease

Author

Buay Deng, Dominican University of CaliforniaFollow

Graduation Year

2021

Document Type

Master's Thesis

Degree

Master of Science

Program

Biological Science

Program Director

Meredith Protas PhD

First Reader

Julie Andersen, PhD

Second Reader

Manish Chamoli PhD

Abstract

Alzheimer’s disease (AD) is the most common form of dementia in the world and currently affects more than 50 million people and has no cure to date. One of its major neuropathological hallmarks is the presence of senile plaques—formed from Amyloid-β (Aβ) oligomers. Aβ has also been associated with the development of cellular senescence in preclinical AD models, suggesting that cellular senescence may be mechanistically involved in disease progression. Cellular senescence is a stress response that occurs when cells are exposed to degenerative factors that puts them into permanent cell cycle arrest, this process increases with age. Apolipoprotein E (ApoE) is a lipoprotein that is mostly produced by astrocytes and is used to transport cholesterol to neurons and exist in 3 genetic isoforms, ApoE (E4, E3 and E2). Where the ApoE4 allele is a major genetic risk factor for Late Onset AD and ApoE2 allele is seen as the neuroprotective allele. There is now growing literature that cellular senescence may be a factor for the onset of AD, and that each APOE isoform is affected by cellular senescence differently. This has led me to test the hypothesis that Apoe4 astrocytes are more likely to develop a senescence like state when exposed to Aβ oligomers compared to ApoE2 astrocytes.

Though preliminary, the data presented in this thesis suggest that ApoE4 may increase susceptibility of astrocytes to develop cellular senescence in a cell autonomous fashion. Specifically, we examined many makers and features of cellular senescence (including, mitochondrial dysfunction,IL-6 secretion, increased p16/p21 expression and decreased LaminB1 expression) in primary mouse astrocytes carrying either the Apoe4 or the Apoe2 allele (an allele which confers AD protection). Our data demonstrate that cultured Apoe4 astrocytes demonstrate increased susceptibility to undergo senescence when exposed to Aβ oligomer, while Apoe2 astrocytes are more resilient to Aβ-induced senescence.