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Investigating the potential of human brain tissue and patient fibroblast derived small extracellular vesicles in Alzheimer's disease research

Youd, SP

Authors

SP Youd



Contributors

GL Lace-Costigan
Supervisor

Abstract

Alzheimer’s disease is the most common cause of dementia. Alzheimer’s disease is a
progressive and irreversible neurodegenerative disease leading on to a decline in cognitive
function causing language, memory and behavioural impairment. The two famous
pathological hallmarks involved in Alzheimer’s disease are the β-amyloid plaques and
intraneuronal neurofibrillary tangles. The abnormal protein accumulation increases as the
disease progresses with the molecular mechanisms underlying the spread of abnormal
protein remaining unclear. Recent research suggests that small extracellular vesicles are
involved in the spread of hyperphosphorylated tau and are thought to act as a prion within
the brain causing normal healthy tau to become pathogenic tau. Small extracellular vesicles
are secreted by all cell types including, brain tissue and they have the ability to pass through
the blood brain barrier. This study focuses on exploring the potential use of human patient
derived skin fibroblast and human brain tissue derived small extracellular vesicles as a tool
to identify dementia biomarkers and to shed light on the disease process. sEVs from human
brain tissue and fibroblast were isolated using exo-spin methodology, the sEVs were
characterised using immunoblotting and nano-particle tracking analysis. sEV were
successfully isolated from human brain tissue from both age-related and Alzheimer’s
disease cases using CD9, CD63, Flotillin-1 and calnexin antibodies but were not successfully
isolated from fibroblast cells. From the whole brain homogenates and sEV fractions further
antibodies were explored, hyperphosphorylated tau (AT8) and autophagy marker - p62. The
p62 antibody was detected in both samples however, AT8 was only detected in sEVs
fractions. Immunohistochemistry was used to further investigate the p62 detection across
different braak groups and to explore if there’s any positive correlation between the
intensity of the stain with the different braak groups. After scoring the slides and
dichotomising the data, it was shown the intensity increased as the braak group increased.
A chi-squared test deemed the results as significant however, due to lack of samples the
results were deemed as unreliable. This study suggests that sEVs can be extracted from
human brain tissue and therefore, is able to help further sEV research studies to overcome
dementia by using sEVs as a way to differentiate between different disease types.

Citation

Youd, S. (2023). Investigating the potential of human brain tissue and patient fibroblast derived small extracellular vesicles in Alzheimer's disease research. (Dissertation). University of Salford

Thesis Type Dissertation
Deposit Date May 2, 2023
Publicly Available Date Mar 29, 2024
Award Date Feb 6, 2023

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