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Pro-inflammatory Cytokine Tumor Necrosis Factor Alpha (TNF-α) Inhibits Beta-amyloid Phagocytosis
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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Corticosterone Administration After Early Adolescent Stress Selectively Blocks Stress-induced Potentiation and Incubation of Morphine Place Preference in Adulthood
Opioid use disorder (OUD) is a large public health concern within the United States. A significant predictor of anxiety and substance abuse disorders in adulthood is childhood or adolescent trauma – psychological or physical. Here we explore the longitudinal effects of early adolescent stress, and the treatment thereof, on the rewarding properties of opioids in adulthood. Using various stressors on mice during early adolescence (PND 30-31), we test the effects of the stress on the rewarding properties of morphine in adulthood (PND 72). To assess morphine reward, we use morphine-induced conditioned place preference (CPP) paradigm in which the motivational properties of morphine are repeatedly paired with a neutral context, that can later elicit an approach behavior toward the morphine-paired context. The effects of stress during adolescence have a long-term effect on potentiating CPP into adulthood. However, no study, to our knowledge, has investigated the effects of treatment interventions post-adolescent stress to alleviate the detrimental effects of stress on both the memory of the stressor and the increased rewarding properties of drugs. A current treatment intervention after trauma in clinical populations is hydrocortisone, a steroid hormone which has shown to be successful at reducing PTSD symptoms three-months after the trauma exposure. We found that the rodent equivalent of hydrocortisone, corticosterone, administration after stress in adolescence selectively ameliorates the impact of the stressor and normalized morphine preference to levels comparable to non-stressed controls. These findings help to uncover potential treatments to aid in the prevention of addictive behaviors.
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What All the Buzz is About: ADAR Editing Landscapes in Drosophila and Human Brains
RNA editing, specifically, adenosine to inosine deamination catalyzed by adenosine acting on RNA enzymes (ADAR editing) plays a key role in increasing neural transcriptome diversity by expanding the number of distinct functional proteins. Changes in ADAR editing of specific genes have been documented in neurodegeneration, including Alzheimer and Parkinson’s diseases, as well as major mental health disorders. By using comparative genomics approaches, we identified orthologous and homologous editing target genes shared between two genomes. We are currently comparing their editing status across different neural populations in two species, as well as between healthy and disordered individuals. The contributions of multiple ADAR loci in human versus that of a single ADAR locus in Drosophila will also be examined. The obtained results will provide insights into the nuanced spatio-temporal regulation of editing patterns in the brain by contrasting editing patterns between human candidate target genes and those edited in Drosophila brain.
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Time-dependent Aggregation of β-amyloid Alters Phagocytosis by Human Microglial Cells
Alzheimer’s disease is an age-related neurodegenerative disease characterized by the accumulation of extracellular beta-amyloid protein and intracellular tau protein, both of which are correlated to neuronal toxicity. Beta-amyloid peptides are known to self-aggregate after cleavage by β-secretase from smaller oligomerized species into large insoluble plaques. These plaques are a hallmark of Alzheimer’s disease and have been shown to vary in size with increased incubation time. Our interest is focused on the removal of β-amyloid by microglial cells from the brain. Microglia are the brain’s immunological cells that are responsible for the clearance of dysfunctional proteins in the brain as well as acting as key regulators of inflammation in the brain. Our hypothesis stands that as β-amyloid aggregates into larger protein species, phagocytosis decreases due to changes in the peptide structure as well as the increase in size. Phagocytosis was then assessed after exposure via transmission confocal microscopy as well as flow cytometry. Collectively, our data show that β-amyloid phagocytosis decreases with larger β-amyloid aggregates, suggesting methods to disaggregate peptides from large plaques could promote clearance.
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