Browsing by Author "Johnson, Sherika N."

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    Acute Communication Between Microglia and Nonparenchymal Immune Cells in the Anti-Aβ Antibody-Injected Cortex
    (Society for Neuroscience, 2025-01-29) Foley, Kate E.; Weekman, Erica M.; Krick, Katelynn E.; Johnson, Sherika N.; Sudduth, Tiffany L.; Wilcock, Donna M.; Neurology, School of Medicine
    Anti-Aβ immunotherapy use to treat Alzheimer's disease is on the rise. While anti-Aβ antibodies provide hope in targeting Aβ plaques in the brain, there still remains a lack of understanding regarding the cellular responses to these antibodies in the brain. In this study, we sought to identify the acute effects of anti-Aβ antibodies on immune responses. To determine cellular changes due to anti-Aβ antibody exposure, we intracranially injected 14 mo APP male and female mice with anti-Aβ IgG1 (6E10) or control IgG1 into the cortex. After 24 h or 3 d, we harvested the cortex and performed a glial cell-enriched preparation for single-cell sequencing. Cell types, proportions, and cell-to-cell signaling were evaluated between the two injection conditions and two acute timepoints. We identified 23 unique cell clusters including microglia, astrocytes, endothelial cells, neurons, oligos/OPCs, immune cells, and unknown. The anti-Aβ antibody-injected cortices revealed more ligand-receptor (L-R) communications between cell types, as well as stronger communications at only 24 h. At 3 d, while there were more L-R communications for the anti-Aβ antibody condition, the strength of these connections was stronger in the control IgG condition. We also found evidence of an initial and strong communication emphasis in microglia-to-nonparenchymal immune cells at 24 h, specifically in the TGFβ signaling pathway. We identify several pathways that are specific to anti-Aβ antibody exposure at acute timepoints. These data lay the groundwork for understanding the brain's unique response to anti-Aβ antibodies.
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    Atorvastatin rescues hyperhomocysteinemia-induced cognitive deficits and neuroinflammatory gene changes
    (BMC, 2023-09-01) Weekman, Erica M.; Johnson, Sherika N.; Rogers, Colin B.; Sudduth, Tiffany L.; Xie, Kevin; Qiao, Qi; Fardo, David W.; Bottiglieri, Teodoro; Wilcock, Donna M.; Neurology, School of Medicine
    Background: Epidemiological data suggests statins could reduce the risk of dementia, and more specifically, Alzheimer's disease (AD). Pre-clinical data suggests statins reduce the risk of dementia through their pleiotropic effects rather than their cholesterol lowering effects. While AD is a leading cause of dementia, it is frequently found co-morbidly with cerebral small vessel disease and other vascular contributions to cognitive impairment and dementia (VCID), which are another leading cause of dementia. In this study, we determined if atorvastatin ameliorated hyperhomocysteinemia (HHcy)-induced VCID. Methods: Wild-type (C57Bl6/J) mice were placed on a diet to induce HHcy or a control diet each with or without atorvastatin for 14 weeks. Mice underwent novel object recognition testing before tissue collection. Plasma total cholesterol and total homocysteine as well as related metabolites were measured. Using qPCR and NanoString technology, we profiled glial cell-associated gene expression changes. Finally, microglial morphology, astrocyte end feet, and microhemorrhages were analyzed using histological methods. Results: Atorvastatin treatment of HHcy in mice led to no changes in total cholesterol but decreases in total homocysteine in plasma. While HHcy decreased expression of many glial genes, atorvastatin rescued these gene changes, which mostly occurred in oligodendrocytes and microglia. Microglia in HHcy mice with atorvastatin were trending towards fewer processes compared to control with atorvastatin, but there were no atorvastatin effects on astrocyte end feet. While atorvastatin treatment was trending towards increasing the area of microhemorrhages in HHcy mice in the frontal cortex, it only slightly (non-significantly) reduced the number of microhemorrhages. Finally, atorvastatin treatment in HHcy mice led to improved cognition on the novel object recognition task. Conclusions: These data suggest that atorvastatin rescued cognitive changes induced by HHcy most likely through lowering plasma total homocysteine and rescuing gene expression changes rather than impacts on vascular integrity or microglial changes.
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    Glial changes as result of cerebral amyloid angiopathy progression
    (Wiley, 2025-01-03) Krick, Katelynn E.; Johnson, Sherika N.; Rogers, Colin B.; Sudduth, Tiffany L.; Weekman, Erica M.; Wilcock, Donna M.; Anatomy, Cell Biology and Physiology, School of Medicine
    Background: Cerebral Amyloid Angiopathy (CAA) occurs at the intersection of Alzheimer’s disease and vascular contributions to cognitive impairment and dementia (VCID). In the human brain it occurs when amyloid beta (Aβ) aggregates in small/medium‐sized cerebral blood vessels, which contribute to hypoperfusion and cognitive decline by altering vascular function and integrity. The current study seeks to track the progression of CAA and associated neuroinflammation and glial cell changes in Tg2576 mice. Method: Tg2576 mice were aged to 8‐, 14‐, 20‐, and 27‐months and assessed for CAA pathology via histology. Gene expression was evaluated in hippocampal tissue by qPCR and posterior cortex by nanostring (ncounter Mouse Neuroinflammation and Mouse CVD Pathophysiology panels; in progress) to compare 8‐ and 20‐month APP and wildtype groups. Protein expression was evaluated via digital spatial profiling in the same APP mice, grouped by age or CAA presence compared to wildtype controls. CAA presence was defined as Aβ surrounding lectin‐positive vessels. Regions of interest were categorized as either positive or negative for CAA based on this criterion. Result: Congophillic plaque deposition along the vasculature increased in width, length, and area in a time dependent manner in both the frontal cortex and hippocampus. Astrocyte marker GFAP and proinflammatory receptor TNFR1 gene expression both increased at 20 months compared to 8 months in the APP group. Of the protein profile assessed (Mouse Neural Cell Profiling and Mouse Glial Cell Subtyping), the most consistent changes were found in astrocyte markers. Both Aldh1l1 and S100B were increased at 20 months compared to 8 months of age in both APP and WT mice. GFAP protein expression was found to increase with both age and CAA. Conclusion: This study showed increased vascular amyloid deposition and astrocyte gene and protein expression over time, further supporting a role for astrocytes in etiology and/or reaction to CAA.