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Using an in-vivo Drosophila model to determine the influence of age and hyperphosphorylated tau on neuronal structure and function

Using an in-vivo Drosophila model to determine the influence of age and hyperphosphorylated tau on neuronal structure and function
Using an in-vivo Drosophila model to determine the influence of age and hyperphosphorylated tau on neuronal structure and function
Although ageing is considered the leading risk factor for Alzheimer’s Disease (AD), knowledge of what occurs to neuronal morphology and cytoskeletal structures during physiological ageing is poor. This is interesting due to the known influence of cytoskeletal destabilisation in AD pathogenesis. Further, how age-related increases in tau phosphorylation influence neuronal morphology outside of disease is yet to be uncovered. I aimed to investigate how ageing and age-related increases in tau phosphorylation influence the morphology of neurons and the contribution of cytoskeletal destabilisation to such changes. I take advantage of the short life span and superior genetic tractability of Drosophila Melanogaster to investigate how physiological ageing influences neuronal morphology and if age-related increases in tau hyperphosphorylation can recapitulate morphological abnormalities that occur with age. I have developed optical imaging protocols using high-resolution Structured-Illumination-Microscopy and confocal line scanning microscopy to document morphological changes in the somatodendritic and axonal neuronal compartments of GFP-labelled OR47B olfactory receptor neurons. Through this, I find that neuronal morphological changes accompany physiological ageing. This includes reductions in cell body, dendrite and axonal size and the appearance of dendritic and axonal swellings. Although the microtubules of these neurons appear compromised with age, dietary supplementation of a microtubule stabilising peptide (NAPVSIPQ) only partially rescues age-related morphological changes at the axonal but not somatodendritic compartments. Moreover, the expression of human tau within young OR47B neurons demonstrates morphology that closely mirrors young controls. However, the targeted expression of a phosphomimicking designer mutant of human tau in young circuits, modelling age-related increases in tau phosphorylation, phenocopies morphological changes that are seen in physiologically aged neurons. This includes reductions in cell body and axonal size, accumulation of axonal and dendritic swellings and additionally the loss of cell bodies. Cytoskeletal fortification via NAP supplementation partially recovers cell death and morphological changes at the axon but, similar to aged neurons, does not influence somatodendritic morphology. In conclusion, neurons suffer from age-related morphological abnormalities that are phenocopied in young circuits through hyperphosphorylated tau. Cytoskeletal destabilisation is one of the drivers of these morphological changes but other mechanisms such as protein accumulation/aggregation likely contribute equally. Such insults might increase vulnerability to neurodegenerative diseases and functional impairment as we age and this work has revealed important hallmarks of physiological ageing which might lead to aberrant processes. However, more must be done to understand the additional triggers and functional consequences of age and phospho-tau-induced morphological abnormalities.
University of Southampton
Richardson, Bradley
08014d5f-1543-4b3a-aa92-428827312cd4
Richardson, Bradley
08014d5f-1543-4b3a-aa92-428827312cd4
Mudher, Amritpal
ce0ccb35-ac49-4b6c-92b4-8dd5e78ac119
Wijnen, Herman
67e9bc5d-de6e-44ec-b4c2-50b67c5bc79d

Richardson, Bradley (2024) Using an in-vivo Drosophila model to determine the influence of age and hyperphosphorylated tau on neuronal structure and function. University of Southampton, Doctoral Thesis, 238pp.

Record type: Thesis (Doctoral)

Abstract

Although ageing is considered the leading risk factor for Alzheimer’s Disease (AD), knowledge of what occurs to neuronal morphology and cytoskeletal structures during physiological ageing is poor. This is interesting due to the known influence of cytoskeletal destabilisation in AD pathogenesis. Further, how age-related increases in tau phosphorylation influence neuronal morphology outside of disease is yet to be uncovered. I aimed to investigate how ageing and age-related increases in tau phosphorylation influence the morphology of neurons and the contribution of cytoskeletal destabilisation to such changes. I take advantage of the short life span and superior genetic tractability of Drosophila Melanogaster to investigate how physiological ageing influences neuronal morphology and if age-related increases in tau hyperphosphorylation can recapitulate morphological abnormalities that occur with age. I have developed optical imaging protocols using high-resolution Structured-Illumination-Microscopy and confocal line scanning microscopy to document morphological changes in the somatodendritic and axonal neuronal compartments of GFP-labelled OR47B olfactory receptor neurons. Through this, I find that neuronal morphological changes accompany physiological ageing. This includes reductions in cell body, dendrite and axonal size and the appearance of dendritic and axonal swellings. Although the microtubules of these neurons appear compromised with age, dietary supplementation of a microtubule stabilising peptide (NAPVSIPQ) only partially rescues age-related morphological changes at the axonal but not somatodendritic compartments. Moreover, the expression of human tau within young OR47B neurons demonstrates morphology that closely mirrors young controls. However, the targeted expression of a phosphomimicking designer mutant of human tau in young circuits, modelling age-related increases in tau phosphorylation, phenocopies morphological changes that are seen in physiologically aged neurons. This includes reductions in cell body and axonal size, accumulation of axonal and dendritic swellings and additionally the loss of cell bodies. Cytoskeletal fortification via NAP supplementation partially recovers cell death and morphological changes at the axon but, similar to aged neurons, does not influence somatodendritic morphology. In conclusion, neurons suffer from age-related morphological abnormalities that are phenocopied in young circuits through hyperphosphorylated tau. Cytoskeletal destabilisation is one of the drivers of these morphological changes but other mechanisms such as protein accumulation/aggregation likely contribute equally. Such insults might increase vulnerability to neurodegenerative diseases and functional impairment as we age and this work has revealed important hallmarks of physiological ageing which might lead to aberrant processes. However, more must be done to understand the additional triggers and functional consequences of age and phospho-tau-induced morphological abnormalities.

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More information

Published date: 2024
Additional Information: Raw data for this thesis is held (physical copy) by the Primary Supervisor

Identifiers

Local EPrints ID: 494805
URI: http://eprints.soton.ac.uk/id/eprint/494805
PURE UUID: c4be31f8-ac27-44f2-b387-7978aa86248a
ORCID for Herman Wijnen: ORCID iD orcid.org/0000-0002-8710-5176

Catalogue record

Date deposited: 15 Oct 2024 17:04
Last modified: 16 Oct 2024 01:48

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Contributors

Thesis advisor: Amritpal Mudher
Thesis advisor: Herman Wijnen ORCID iD

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