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Thesis
Investigating microglial innate immune responses to amyloid-beta (1-42) and murine betacoronavirus (MHV-A59)
Master of Science (M.S.), Drexel University
Aug 2021
DOI:
https://doi.org/10.17918/00000862
Abstract
Microglia are resident innate immune cells of the central nervous system (CNS) that sense pathogen-associated molecular pattern (PAMPs) and damage associated molecular patterns (DAMPs) during both infectious and sterile insults. Although toll like receptors (TLRs) play key roles in microglia responses by promoting tissue repair and contributing to CNS homeostasis, TLRs deregulation may mediate chronic inflammation contributing to neurodegeneration. Amyloid-beta (A[beta]) is an antimicrobial peptide protein that accumulates in senile plaques, a hallmark of Alzheimer's disease (AD). Microglia recognize and phagocytose A[beta], which activate the cell and result in a proinflammatory response. The role of TLRs in the response to A[beta] is ill defined. TLR2 and TLR4 sense lipopeptides and LPS, respectively, and have been involved in AD pathogenesis. Recently, upregulation of the expression of the double-stranded dsRNA sensor TLR3 was reported in AD human brains. However, whether TLR3 is activated in AD brains remains undefined. In Aim 1 studies, we test the hypothesis that A[beta]1-42 stimulation induces TLR3 activation in murine microglia. In Aim 2 studies, we investigated microglial TLRs responses to murine betacoronavirus mouse hepatitis virus (MHV)-A59, a neurotropic positive RNA virus that induces neuroinflammation and chronic demyelination. Interestingly, our findings demonstrated that microglia uptake of A[beta](1-42) induced phosphorylation of TLR3 at residue Y759, the hallmark of the TLR3 pathway activation. Moreover, we found that immune responses to MHV-A59 rely upon TLR signaling, which varies depending on the pathway activated. Our results highlight TLR3 activation as a novel response to A[beta](1-42) stimulation, and identify the TLRs sensing [beta]CoV infection in microglia.
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Details
- Title
- Investigating microglial innate immune responses to amyloid-beta (1-42) and murine betacoronavirus (MHV-A59)
- Creators
- Olivia Qiaofen Cipollini
- Contributors
- Fred C. Krebs (Advisor)
- Awarding Institution
- Drexel University
- Degree Awarded
- Master of Science (M.S.)
- Publisher
- Drexel University; Philadelphia, Pennsylvania
- Number of pages
- vii, 97 pages
- Resource Type
- Thesis
- Language
- English
- Academic Unit
- Microbiology and Immunology; College of Medicine; Drexel University
- Other Identifier
- 991015473892104721