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Investigating the Relationship between Small Extracellular Vesicular MicroRNA Cargoes and Autophagic Alterations of Alzheimer's Disease and Frontotemporal Dementia

Morgan, Joseph

Investigating the Relationship between Small Extracellular Vesicular MicroRNA Cargoes and Autophagic Alterations of Alzheimer's Disease and Frontotemporal Dementia Thumbnail


Authors

Joseph Morgan



Abstract

Dementia is caused by various diseases, such as Alzheimer’s disease (AD) and frontotemporal dementia (FTD), leading to cognitive deficiencies, behavioural impacts, and symptoms impairing daily functioning. Pathologically, AD and FTD involve neurotoxic protein accumulation (amyloid-β, tau, TDP-43) alongside impaired autophagic mechanisms, leading to proteostatic imbalance and neuronal cell death. Small extracellular vesicles (sEVs) are implicated in the transsynaptic spread of pathological proteins in multiple neurodegenerative diseases and may also carry potential biomarkers of AD and FTD. Having previously shown to carry AD-linked proteins, other cargoes such as FTD and autophagy-associated proteins and microRNA (miRNA) are less studied. These regulatory species can cross the blood brain barrier and may shed light on disease processes and differentiate between different dementia sub-groups. Currently, no early method of AD or FTD diagnosis exists, and with rising cases of dementia, there is an urgent need for diagnostic solutions. This study aims to identify specific miRNA sEV cargo signatures to differentiate dementia subtypes whilst identifying potential pathways of therapeutic interest. Here, sEVs isolated from AD and FTD mutations (GRN, MAPT and C9orf72) post-mortem brain tissue was characterized using fluorescent nanoparticle tracking analysis, western blotting, and transmission electron microscopy. Next, isolated miRNA samples were analysed using real-time quantitative PCR (RT-qPCR) and small RNA-sequencing, with sEV protein cargoes examined using western blotting. Lastly, SH-SY5Y cell lines were treated with FTD-C9orf72 brain-derived sEVs to observe pathogenic causes such as TDP-43 mislocalisation. Using RT-qPCR, autophagic and cluster-associated miRNA displayed variation between dementia subtypes. Additionally, small RNA-sequencing revealed 12 AD, 7 GRN, 42 MAPT and 24 C9orf72 differentially expressed miRNAs. Analysis of pathogenic and autophagic protein cargoes showed toxic TDP-43 in GRN and C9orf72 sEVs, yet tau (Ser-202/Thr-205) was only found in AD sEVs; with Beclin-1 increased in AD, MAPT, and C9orf72 sEVs, whilst LC3B-II decreased in all FTD mutation sEVs. Fluorescent microscopy confirmed the uptake of no disease and diseased sEVs uptake, causing TDP-43 mislocalisation. Potential miRNA cargo variations has been identified which require further research to validate them as biofluid biomarkers.

Thesis Type Thesis
Acceptance Date Apr 29, 2025
Online Publication Date Jun 10, 2025
Deposit Date Apr 29, 2025
Publicly Available Date Jul 11, 2025
Award Date May 29, 2025

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