Abstract
Tauopathies are a family of neurodegenerative disorders in which highly phosphorylated and aggregated tau proteins are deposited as neurofibrillary pathology. Primary tauopathies, in which tau forms the dominant pathology, include progressive supranuclear palsy (PSP) and Pick’s disease (PiD). Alzheimer’s disease (AD), the most common cause of dementia, is considered a secondary tauopathy since -amyloid peptides are deposited in plaques alongside tau deposits in the form of neurofibrillary tangles. Tauopathies are a heterogeneous group of disorders with variations in the brain regions affected, the isoform and structure of the deposited tau, and the type of neural cells that tau is deposited, all of which combine to influencing clinical outcomes.Preliminary data from this laboratory, that is extended in this thesis, showed that there is some regional specificity in the deposition of tau isolated from postmortem tauopathy brain, following its peripheral administration to mice expressing wild-type human tau in the absence of mouse tau (htau mice). This suggested that there may be regional vulnerability to different species of tau. In addition, a close association of astrocytes with large tau deposits was noted. This suggested that astrocytes respond to tau and may contribute to tau spread. Indeed, recent work has shown that astrocytes can internalise different forms of recombinant and brain-derived tau.
To investigate this further, a human induced pluripotent stem cell (iPSC)-astrocyte model was established and characterised in comparison to induced neural precursor cell-astrocytes (iNPC-astrocytes). iPSC-astrocytes, more so than iNPC-astrocytes, showed the progressive appearance of mature astrocyte gene expression and morphological changes. iPSC-astrocytes were therefore selected for further investigation. Treating iPSC-astrocyte with tau aggregates isolated from postmortem AD brain showed that astrocytes efficiently internalise human tau, clearing these aggregates slowly over time. Moreover, internalised tau aggregates appeared to localise with high levels of GFAP and S100B, two astrocytic molecules that have previously been associated with progression of tauopathy pathology. There were variations in the rate of tau uptake and clearance that are likely related to molecular properties of the human tau, with some further indications of varied seeding ability of endogenous astrocytic tau. Astrocytes showed varied changed in gene expression in response to tau uptake including in genes implicated in astrocyte reactivity, protein degradation and clearance. However, when astrocyte conditioned medium from astrocytes exposed to tau aggregates was collected and applied to iPSC-neurons, there were no overt changes in neuron health.
Together, these data demonstrate that astrocytes respond to the presence of tau aggregates in their local environment. This data adds to a growing body of evidence that astrocytes may contribute to tau spread by internalising tau aggregates from extracellular spaces or tau that is contained within apoptotic cells. It is not clear whether this is a protective response or if the astrocytes may release seed-competent tau species into media to facilitate its spread. Several signalling pathways were identified for further investigation to determine the precise mechanisms involved in this function of astrocytes, and it will be of interest to determine how the scale of these changes relates to molecular characteristics of different tau species.
| Date of Award | 1 Dec 2022 |
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| Original language | English |
| Awarding Institution |
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| Supervisor | Beatriz Gomez Perez-Nievas (Supervisor) & Wendy Noble (Supervisor) |