Spires-Jones, Tara

Durrant, Claire

Keavey, Lois

2024-10-29T15:23:46Z

2024-10-29T15:23:46Z

2023-11-25

Tau protein is generally considered to exist natively as an unfolded protein, functioning to stabilise microtubules in axons. Posttranslational modifications such as phosphorylation can influence its aggregation and oligomerisation, resulting in the formation of pathological forms of tau such as hyperphosphorylated and oligomeric tau, and neurofibrillary tangles. In tauopathies such as Progressive Supranuclear Palsy (PSP), patients experience difficulties with balance, ocular disturbance and dysphagia, as well as cognitive decline. Tau sequentially appears in a spatiotemporal pattern through functionally connected regions of the brain, with earlier presentation in the substantia nigra, and later in the frontal cortex in PSP. In this project we have utilised a sub-diffraction limit microscopy technique called array tomography, and immunohistochemical staining of paraffin embedded human post-mortem tissue. Through analysis of colocalization of pathological tau, pre-synapses, reactive astrocytes and microglia in the substantia nigra and frontal cortex, we investigated the accumulation of pathological tau at synapses, gliosis and synaptic engulfment by glia in PSP compared to age and sex matched controls. Results from array tomography suggest there is increased accumulation of hyperphosphorylated tau at pre-synapses in substantia nigra (type 3 ANOVA, p<0.05), plus increased colocalization of reactive astrocytes with pre-synapses in this region (type 3 ANOVA p<0.05). Human paraffin staining suggested that though no direct difference was observed between PSP and control cohorts, differences in colocalization of tau and pre-synapses with reactive astrocytes and microglia between PSP and control brains were found to be effects of the different brain regions studied, and disease progression with age. Diaminobenzidine (DAB) staining with AT8 allowed observation of increased burden of hyperphosphorylated tau in PSP compared to controls in both frontal cortex and substantia nigra (type 3 ANOVA p<0.05) and observation of the variation of tau burden across both PSP and control cases. Linear mixed effects models (type 3 ANOVA) were used for all analyses. By illustrating the accumulation of pathological tau at pre-synapses and reactive astrocytes, we have built upon previous evidence of tau accumulation within the PSP brain, supporting the hypothesis that synaptic accumulation of tau may lead to dysfunction, and loss of synapses.

https://hdl.handle.net/1842/42382

http://dx.doi.org/10.7488/era/5076

en

The University of Edinburgh

Tau protein

Progressive Supranuclear Palsy (PSP)

Diaminobenzidine (DAB)

unfolded protein

microtubules in axons

Human paraffin staining

Investigating mechanisms of synaptic loss in progressive supranuclear palsy

Thesis or Dissertation

Doctoral

MSc(R) Master of Science by Research