| Abstract |
Alzheimer’s disease is a progressive neurodegenerative disease that affects millions of people worldwide. Beta-amyloid peptides are cleaved from the amyloid precursor protein (APP) and then undergo additional cleavage by alpha secretase to become a soluble 40 amino acid protein. However, when cleaved by beta-secretase rather than alpha secretase, a 42 amino acid species is produced known as beta-amyloid1-42 which spontaneous self aggregates into large insoluble plaques over time. The aggregation of beta-amyloid closely correlates with the promotion of neuroinflammatory signaling. Microglia, the brain's phagocytic immune cells, are responsible for the clearance of beta-amyloid in the brain as well as neuroinflammatory signaling. It has been observed that tumor necrosis factor alpha (TNF-α) is one of the earliest proinflammatory cytokines to be upregulated in contest to Alzheimer’s disease. Our major hypothesis stands that as beta-amyloid aggregates into larger plaque-like species, clearance of beta-amyloid decreases due to its size and altered peptide structure. TNF-α is believed to have a role in the phagocytosis of beta-amyloid. However, as aggregation occurs, it is unclear what effect TNF-α has on the promotion of clearance. We will test the role of TNF-α in human microglial cells. Therefore, we propose that TNF-α inhibits beta-amyloid phagocytosis when the proinflammatory cytokine TNF-α is upregulated, TNF-α expression is exacerbated as oligomerization increased and phagocytosis is further diminished.
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| Modified Abstract |
Alzheimer’s disease is a progressive neurodegenerative disease that affects millions of people worldwide. After beta-amyloid peptides are cleaved from their precursor protein, they can form soluble monomers that readily aggregate into larger protein species. This aggregation leads to large insoluble plaques which are neurotoxic and seemingly unable to be cleared by microglia, the brain’s immune cells. Beta-amyloid aggregates interact with microglia which upregulate pro-inflammatory cytokine signaling. One of the earliest cytokines is tumor necrosis factor alpha (TNF-α). TNF-α has been shown to modify phagocytosis and promote the signaling of upstream pro-inflammatory cytokines, which is critical to regain brain homeostasis. Therefore, we propose that TNF-α inhibits beta-amyloid phagocytosis when the proinflammatory cytokine TNF-α is upregulated, TNF-α expression exacerbated as oligomerization increased and phagocytosis is further diminished.
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