Thermal response of amyloidogenic elements in cultured N2a cells: potential relevance to Alzheimer’s disease pathology

• Author / Creator

  Schmaus, Andrew

• Alzheimer’s disease (AD) weighs a large burden on health care systems, families and caregiving networks around the world. It is the most common dementia afflicting elderly individuals, and causes many debilitating symptoms, including memory loss, mood swings and confusion which progress in severity as the individual declines throughout the disease course. Amyloid-β (Aβ) plaques and tau neurofibrillary tangles (NFTs) are key features of AD, as these insoluble aggregates deposit themselves and spread throughout the brains of AD patients, causing loss of neuronal structure and function and eventual death. Familial AD (FAD) is the less prevalent but more defined form, as genetic mutations drive disease processes. Alternatively, sporadic disease (SAD) is multifactorial in nature, with a complex interplay between a variety of risk factors guiding pathogenesis. A newly emerging risk factor has been posited to contribute to AD: environmental temperature. So far, hypothermia has been studied in the context of tau, while there is not much known about how a reduced temperature can influence the amyloidogenic processes that lead to Aβ production.Thus, in the present study, we utilized a cell culture system to investigate the effects of different ambient temperatures on amyloid precursor protein (APP) metabolism. Murine neuroblastoma cells harboured either endogenous mouse APP (N2a) or had the human Swedish APP transgene expressed (N2a-APP). We exposed these cells to hypothermic (27°C), normothermic (37°C), or hyperthermic (40°C) for either 6, 12, or 24 hours and evaluated cellular processes associated with APP metabolism by a variety of methods. The data obtained throughout this project implicate environmental temperature as capable of influencing APP metabolism, as low temperature caused accumulation of APP α/β-C-terminal fragments as well as a decrease in secreted Aβ1-40/42. Some of these changes may be due to a decrease in the efficiency of the cellular clearance mechanisms associated with the removal of these APP products. We also note alterations in the endolysosomal autophagic system, with an increase in LC3-II, as well as a qualitative increase in the colocalization of Aβ with endolysosomal autophagic constituent proteins LC3 and LAMP1 at hypothermic temperatures. These results obtained in our in vitro hypothermia model describe a temperature-dependent effect on APP processing that may be relevant to AD pathogenesis.

• Subjects / Keywords

  • Amyloid β
  • Thermoregulation
  • Alzheimer's disease
  • APP metabolism
  • Amyloid precursor protein

• Graduation date

  Fall 2020

• Type of Item

  Thesis

• Degree

  Master of Science

• DOI

  https://doi.org/10.7939/r3-em7v-kk56

• License

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