Saudi Cultural Missions Theses & Dissertations
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Item Restricted Exploring potential glial senescence signatures in Alzheimer’s disease(Saudi Digital Library, 2023-11-01) Allehyany, Bshaier; Matthews, PaulBackground: Glial cells’ ability to maintain homeostasis in the brain and regulate neuroinflammation is altered in Alzheimer’s disease. Senescent glia – glia with irreversible cell cycle arrest, resistance to apoptosis, and pro-inflammatory cytokine secretion – are associated with exacerbated amyloid-β and tau pathology. GLB1 is widely associated with predicting glial senescence in ageing. Aims, objectives, and hypothesis: Using imaging mass cytometry data, we aimed to quantify microglia and astrocytes and identify their potential senescence signatures. We hypothesized that a glial senescence signature, predicted by GLB1 co-expression, exists in AD. Methods: Using in-house-generated imaging mass cytometry data from the mid-temporal gyrus of post-mortem brain tissue, cell counts of Iba-1-positive microglia and GFAP-positive astrocytes were determined in AD and control cases. The expression of senescence markers, and the co-expression of GLB1 in senescence-expressing glia were investigated. Independent sample t-tests with an FDR correction were used for between-group comparisons (or the Mann–Whitney U test if data failed the normality test). Results: There was no significant difference between groups in Iba-1-positive microglia and GFAP-positive astrocyte counts. Iba-1-positive microglia did not show a senescence signature, while GFAP-positive astrocytes showed increased senescence expression in p21, γ-H2AX, and GLB1. Cells positive for GLB1 and other senescence markers only showed a significant increase in GFAP-positive astrocytes. Conclusions and future directions: Reactive astrocytes were associated with a GLB1- associated senescence signature in Alzheimer’s disease, whereas microglia were not. This senescence-like phenotype may suggest the vulnerability of reactive glia to oxidative stress and DNA damage. This work highlights the possibility of targeting GLB1-expressing reactive astrocytes for senescent cell-eliminating drugs – senolytics.7 0Item Restricted YKL-40 PREDICTS TEMPOROPARIETAL GLUCOSE HYPOMETABOLISM AND Aβ DEPOSITION IN ALZHEIMER’S DISEASE TRAJECTORY(Saudi Digital Library, 2023-11-01) Allehyany, Bshaier; Edison, PaulAlzheimer’s disease (AD) biomarkers amyloid-β and tau aggregates have not been effective AD therapeutics, and it is important to investigate other biomarkers for AD to identify novel therapeutic targets that slow disease progression. Glial cell activation markers in the cerebrospinal fluid have recently been associated with AD, especially the astroglial activation marker chitinase-3-like protein 1 (YKL-40) and the microglial activation marker soluble triggering receptor expressed on myeloid cells 2 (sTREM2). Another cerebrospinal fluid marker that has been recently associated with AD is the synaptic dysregulation marker growth associated protein 43 (GAP-43). Despite being associated with amyloid-β and tau pathology, the role of these biomarkers in AD-associated temporoparietal glucose hypometabolism and reductions in grey matter volume is still unclear. This study aimed to investigate the associations between cerebrospinal fluid YKL-40, sTREM2, and GAP-43 and brain glucose hypometabolism and reductions in grey matter volume. Participants (n = 385) were grouped into four conditions: AD, amyloid-positive mild cognitive impairment (MCI), amyloid-negative MCI, and controls. Regional analysis and voxel-level linear regression revealed that YKL-40 could predict temporoparietal glucose hypometabolism in amyloid-positive groups, and that GAP-43 is predictive of different patterns of hypometabolism in the AD group. Only sTREM2 and YKL-40 predicted reduced grey matter volume, but YKL-40 predicted earlier cognitive decline. YKL-40 may be more sensitive to earlier stages of cognitive decline in amyloid-positive participants than the other markers, possibly due to amyloid-induced neuroinflammation and neurodegeneration. However, correlational studies can only give indirect conclusions and future studies are needed to identify direct effects of neuroinflammation and synaptic loss on YKL-40 levels using cell cultures.8 0