Targeting the M1 muscarinic acetylcholine receptor in neurodegeneration

Sarah, Hesse (2023) Targeting the M1 muscarinic acetylcholine receptor in neurodegeneration. PhD thesis, University of Glasgow.

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Alzheimer’s disease (AD) is the most common neurodegenerative disorder, and to date, no disease-modifying treatments exist. The M1 muscarinic acetylcholine receptor (mAChR) is an established therapeutic target for the symptomatic treatment of AD, and drugs activating the M1 mAChR have been shown to improve cognitive decline and behavioural symptoms in several clinical trials. Pre-clinical evidence also suggests that M1 mAChRs may also have disease-modifying effects in neurodegeneration, such as modification of the classical AD hallmarks, amyloid β (Aβ) and tau. Due to the conserved nature of the classic orthosteric binding site of the five mAChR subtypes, targeting one subtype via this binding site specifically has proved challenging. The development of compounds targeting the less conserved allosteric site has enabled significant improvements in subtype selectivity. Chronic dosing with the M1 mAChR positive allosteric modulator (PAM) VU0486846 has demonstrated disease-modifying potential in a murine prion model of terminal neurodegeneration and in an Aβ-based genetic AD model. This thesis aimed to assess the effect of chronic treatment with the M1 mAChR PAM VU0486846 in the rTG4510 tauopathy mouse model. The results show that VU0486846 did not affect the expression of neuropathological markers of disease, such as phosphorylated tau and glial fibrillary acidic protein, but reversed elevated levels of coagulation factor III and cystatin C that were observed in diseased mice when compared to controls. The normalisation of coagulation factor III and cystatin C, which have both been shown to be dysregulated in AD patients, remains an interesting avenue for further research. As part of trying to understand the potential of the M1 mAChR as a drug target, it is crucial to also determine receptor localisation. Therefore, this thesis also aimed to assess M1 mAChR distribution in the brain using a M1-monomeric enhanced green fluorescent protein (meGFP) mouse line, which expresses the meGFP tagged version of the M1 mAChR in the endogenous gene locus. Tissue clearing was used to visualise the receptor and a range of studies was performed to explore the utility of the meGFP-tagged M1 mAChR. Overall, this thesis identified some novel changes following chronic treatment with a M1 mAChR PAM in a tauopathy mouse model, which warrant further investigation to fully evaluate the potential of targeting the M1 mAChR in neurodegeneration.

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Colleges/Schools: College of Medical Veterinary and Life Sciences > School of Molecular Biosciences
Supervisor's Name: Tobin, Prof. Andrew and Bradley, Dr. Sophie
Date of Award: 2023
Depositing User: Theses Team
Unique ID: glathesis:2023-83466
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 02 Mar 2023 14:54
Last Modified: 03 Mar 2023 09:22
Thesis DOI: 10.5525/gla.thesis.83466
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