Glial Expression of Amyloid Precursor Protein (APP) and its Processing Enzymes in the ANPC Mouse Model

  • Author / Creator
    Sasse, Verena A
  • Alzheimer’s disease (AD) is a complex and progressive neurodegenerative disorder believed to be triggered by the accumulation of β-amyloid (Aβ) peptides derived from the proteolytic processing of amyloid precursor protein (APP). The regions primarily affected in AD brains are the hippocampus and cortex, whereas the striatum and cerebellum are relatively spared. Although neurons are considered to be the major source of Aβ proteins in the brain, the activated astrocytes associated with neuritic plaques, the key neuropathological hallmark of AD brains, have also been shown to accumulate Aβ. Growing evidence over the last decades revealed that alterations in the levels and/or subcellular distribution of cholesterol can influence Aβ metabolism and development of AD pathology, but the underlying mechanisms remain unknown. Since cholesterol has been shown to influence Aβ generation, it is of interest to determine whether an accumulation of cholesterol within the endosomal-lysosomal system, the major site of Aβ production, can influence levels and/or processing of APP. Several recent studies have shown that AD exhibits some distinct similarities with Niemann-Pick Type C (NPC) disease – an autosomal recessive disorder caused primarily by loss-of-function mutations in the NPC1 gene. NPC disease, which is neuropathologically characterized by the intracellular accumulation of cholesterol, exhibits tau-positive neurofibrillary tangles and increased levels of Aβ peptides that are also the hallmarks of AD brains. To determine how activated astrocytes express APP and its processing enzymes and therefore may contribute to the overall Aβ burden we used mutant APP transgenic (APP-Tg) mice, mice lacking Npc1 protein (NPC1-null) required for intracellular cholesterol transport, and our recently developed bigenic ANPC mice (mutant APP-Tg mice in the absence of NPC1 protein) that overexpress mutant human APP in absence of Npc1 protein. Our results show that APP and its processing enzymes such as β-secretase BACE1 and components of the γ-secretase complex (Psen1and Pen2) are expressed in a subset of reactive astrocytes in ANPC, APP-Tg and NPC1-null mice but not in age-matched wild-type control mice. The relative number of astrocytes expressing APP and its
    processing enzymes appear more in ANPC>APP-Tg>NPC1-null mice. To further test the significance of cholesterol, we used mice that were treated with the sterol binding agent 2-hydroxypropyl-β- cyclodextrin (2-HPC) that has been shown to promote the removal of the sequestered cholesterol from lysosomes. We observed that reversal of cholesterol accumulation by 2-HPC treatment attenuates the observed glial pathological abnormalities especially in ANPC mice and to a lesser extent in APP-Tg and NPC1-null mice. Additionally, our results indicate a functional interaction between APP and NPC1 genes that may connect both AD and NPC pathologies.
    Collectively, our results indicate that reactive astrocytes may have an important role in the generation of Aβ-peptides in AD-related pathology. Additionally, accumulation of cholesterol within the endosomal-lysosomal system may influence APP levels/processing in the activated astrocytes of the three mutant mouse lines.

  • Subjects / Keywords
  • Graduation date
    Fall 2021
  • Type of Item
  • Degree
    Master of Science
  • DOI
  • License
    This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.