ORCID Profile
0000-0001-8881-6693
Current Organisation
University of Tasmania
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Publisher: Frontiers Media SA
Date: 28-06-2019
Publisher: Elsevier BV
Date: 06-2019
DOI: 10.1016/J.NEUROSCIENCE.2019.04.015
Abstract: Environmental enrichment (EE) has been consistently reported to enhance cognitive function in mouse models of neuropathology. Microglia, implicated in Alzheimer's disease pathology, may mediate this effect. The aim of the present study was to investigate the effect of EE on cognitive function and microglia in mouse models of aging and amyloidosis. Male wild-type (Wt) and APP/PS1 mice were randomly assigned to standard housing (SH) or EE from 12 to 18 months of age. Spatial memory testing was performed using the Y and Barnes maze. Immunohistochemical analysis of Aβ load, Iba1 and CD-68-labeled (phagocytic-type) microglia was examined between conditions. EE from 12 months of age was associated with improved short-term memory performance in APP/PS1 mice, despite no reductions to Aβ load. APP/PS1 mice in SH had significantly increased microglia occupying the neocortex and hippoc us (p = 0.02 p = 0.004, respectively) relative to Wt animals. Microglia labeling was not statistically different between EE-exposed APP/PS1 compared to Wt mice, indicating that EE may attenuate the increased microglial load in aging APP/PS1 mice. APP/PS1 mice from EE had significantly (p = 0.01) higher colocalization of Iba1 and CD-68 labeling, indicative of increased phagocytic microglia compared to mice from SH. The findings of the present study suggest that EE after substantial brain amyloidosis, has the potential to preserve domains of cognitive function, while having no effect on Aβ deposition. The current study demonstrates that EE may attenuate microglia in aging APP/PS1 mice, and may promote alterations in cellular phenotype.
Publisher: Cold Spring Harbor Laboratory
Date: 10-2023
Publisher: Wiley
Date: 22-11-2023
DOI: 10.1002/JNR.25146
Abstract: Stroke therapy has largely focused on preventing damage and encouraging repair outside the ischemic core, as the core is considered irreparable. Recently, several studies have suggested endogenous responses within the core are important for limiting the spread of damage and enhancing recovery, but the role of blood flow and capillary pericytes in this process is unknown. Using the Rose Bengal photothrombotic model of stroke, we illustrate blood vessels are present in the ischemic core and peri-lesional regions 2 weeks post stroke in male mice. A FITC-albumin gel cast of the vasculature revealed perfusion of these vessels, suggesting cerebral blood flow (CBF) may be partially present, without vascular leakage. The length of these vessels is significantly reduced compared to uninjured regions, but the average width is greater, suggesting they are either larger vessels that survived the initial injury, smaller vessels that have expanded in size (i.e., arteriogenesis), or that neovascularization begins with larger vessels. Concurrently, we observed an increase in platelet-derived growth factor receptor beta (PDGFRβ, a marker of pericytes) expression within the ischemic core in two distinct patterns, one which resembles pericyte-derived fibrotic scarring at the edge of the core, and one which is vessel associated and may represent blood vessel recovery. We find little evidence for iding cells on these intralesional blood vessels 2 weeks post stroke. Our study provides evidence flow is present in PDGFRβ-positive vessels in the ischemic core 2 weeks post stroke. We hypothesize intralesional CBF is important for limiting injury and for encouraging endogenous repair following cerebral ischemia.
Publisher: Elsevier BV
Date: 06-2022
DOI: 10.1016/J.TAAP.2022.116025
Abstract: Capillary pericytes have numerous functions important for tissue maintenance. Changes in pericyte function are implicated in diseases such as cancer, where pericyte-mediated angiogenesis contributes to the blood supply that tumors use to survive. Some anti-cancer agents, like imatinib, target platelet-derived growth factor receptor-beta (PDGFRβ). Healthy pericytes rely on PDGFRβ phosphorylation for their survival. Therefore, we hypothesised that pharmacological agents that block PDGFRβ phosphorylation could be used to kill pericytes. We treated human brain vascular pericytes, which express PDGFRβ, with three receptor tyrosine kinase inhibitors: imatinib, sunitinib and orantinib. Imatinib and sunitinib, but not orantinib, inhibited PDGFRβ phosphorylation in pericytes. Imatinib and sunitinib also reduced viability, prevented proliferation, and induced death, while orantinib only blocked pericyte proliferation. Overall, we found that receptor tyrosine kinase inhibitors that block PDGFRβ phosphorylation cause healthy pericytes to die in vitro. While useful in cancer to limit tumor growth, these agents could impair healthy brain pericyte survival and impact brain function.
No related grants have been discovered for Natalie King.