BACKGROUND:

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The blood-brain barrier (BBB) has a critical protective role in maintaining homeostasis for the central nervous system. It acts as a physical barrier and precisely coordinates the transport of molecules and cells between the blood and the brain. However, BBB breakdown has been reported during numerous disease states including dementia disorders, which can cause severe cerebral blood flow dysregulation and neuronal injury. Therefore, effective homeostatic control between multiple cellular subtypes as part of the ‘neurovascular unit’ is essential.

 

One cell in particular that has shown substantial susceptibility to neurodegenerative changes are pyramidal neurons. As in specific dorsolateral prefrontal cortex and hippocampus sub-areas of post-stroke dementia individuals, neuronal volumes were significantly altered compared to aging controls, likely due to vascular mechanisms. Moreover, the adjacent medial prefrontal cortex has previously been suggested as affected with dysregulated sub-cortical connections across numerous aging and dementia states within neuroimaging studies.

In my PhD, I am trying to elucidate how neurovascular cells such as pyramidal neurons become morphologically changed within post-stroke dementia (PSD) as well as other aging-associated dementias. This should hopefully allow us to better understand how PSD changes neuropathologically in this specific brain area and may even help to find new biomarkers that can be applied as potential drug targets or disease hallmarks.

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METHODOLOGY:

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I have used unbiased 3D stereology to assess how individual pyramidal neuron’s morphology becomes changed across different dementias including PSD compared to aging controls. I have additionally utilised immunohistochemistry to quantify potential mechanisms such as mitochondrial dysfunction for why pyramidal neurons might change across subjects. Immunofluorescence staining techniques have also been utilised to evaluate fluorescent intensities of neurovascular cells on frontal brain tissue, as part of optimising antibodies for an Imaging Mass Cytometry (IMC) panel. Antibodies were then individually metal-conjugated and will be applied to frontal brain tissue sections in planned future work.

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RESULTS:

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There is an apparent change in pyramidal neuron soma morphology in terms of volumes and densities, which was significantly different to controls. I have also shown possible mechanistic changes within these neurons and have optimised by immunofluorescence (see pretty pictures below of immunostained astrocytes and blood vessels!) for ~13 antibodies to be utilised in the IMC panel. Each of these antibodies once metal conjugated have then shown a positive signal when run using a beads kit on the HyperIon IMC system.

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FUTURE WORK: 

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I hope to next complete the immunostaining for my IMC panel, which will then need detailed data analysis to elucidate how these neurovascular cells are specifically changed across dementia groups. I further plan on exploring additional possible mechanistic reasons for the observed change in pyramidal neurons across dementias that was found. I would also be quite interested in potentially learning more high-throughput proteomics or RNA sequencing techniques to gain genomic and bigdata insight into possible changes of neurovascular cells within dementia!

 

P.S. I will be running (and aQempHng!) the Great North Run Half-Marathon later this year to raise important funds for Alzheimer’s Society, so any support and kind donations would be very much appreciated: https://www.justgiving.com/fundraising/GreatNorthRun2024-DanJobson

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FUNDED BY:

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CONTACT: 

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