Targeting muscarinic receptors in treating and slowing the progression of neurodegeneration

Bowden, Jessica Elisabeth Kathleen (2024) Targeting muscarinic receptors in treating and slowing the progression of neurodegeneration. PhD thesis, University of Glasgow.

Abstract

Background

Alzheimer’s disease (AD) is a progressive neurodegenerative disease and the leading cause of dementia, which is projected to affect 1 million people by 2030. Despite the recent conditional approval of potential disease-modifying treatments by the Food and Drug Administration, there remains an urgent social and economic need for treatments which not only alleviate symptoms of AD but also slow its clinical progression. Loss of brain cholinergic innervation is a key hallmark of AD; inhibiting the breakdown of acetylcholine at synapses provides short-term symptomatic relief but produces dose-limiting side effects due to overactivation of peripheral receptors. The therapeutic effects of these drugs are largely attributed to increased activation of the M1 muscarinic acetylcholine receptor (mAChR) subtype, which has led to drug discovery programmes aimed at identifying positive allosteric modulators which directly enhance activation of the M1 mAChR to avoid adverse effects mediated by peripheral mAChRs.

M1-selective compounds have shown promise in preclinical studies, including delaying the onset of terminal disease in a prion model of neurodegeneration, but no compounds have yet been approved for clinical use. Translation of preclinical efficacy to effective treatments that slow the progression of AD requires robust biomarkers that can be longitudinally monitored to investigate the ability of drug candidates to modify the course of neurodegenerative disease. AD produces robust and progressive changes in brain oscillatory activity recorded using electroencephalography (EEG) or magnetoencephalography (MEG), which reflect the large-scale coordination of neuronal activity. Consequently, identifying whether animal models of aspects of AD produce similar alterations to neuronal oscillations can support the use of such models for preclinical testing of drug candidates.

Main aims

The first major aim of this thesis was to determine the impact of a model of progressive terminal neurodegeneration on cognition-relevant neuronal oscillations. The second aim was to identify electrophysiological signatures of selectively enhancing the activity of M1 mAChRs. The third aim was to robustly quantify the impact of muscarinic deficit, an additional feature of AD, on neuronal oscillations. The final aim was to assess the impact of potentiating M1 mAChRs on the electrophysiological signatures of muscarinic deficit.

Methods

These studies utilised a wireless electrophysiological recording system and electrodes implanted into the skull to record bulk neuronal activity from the brain surface of mice. This approach was employed to maximise the translatability of findings to human EEG recordings. Progressive terminal neurodegeneration was modelled using a prion intracerebral injection model. One cohort was used for behavioural characterisation and to determine the time to onset of early symptoms and terminal disease. Subsequent cohorts underwent surgical implantation of recording electrodes and weekly electrophysiological recording in the home cage until they reached the terminal disease end point. For pharmacology experiments, wild-type mice were implanted with surface electrodes and underwent recording at timepoints before and after dosing with M1-selective compounds and/or the non-selective muscarinic receptor antagonist, scopolamine.

Outcomes

The prion model exhibited a slowing of peak theta frequency, which is also a key electrophysiological signature of AD, suggesting that this is a marker of neurodegenerative disease progression which may be a useful biomarker for preclinical assessment of the disease modifying potential of drug candidates. The most robust effect of directly activating or enhancing the activation of M1 mAChRs was an increase in gamma power, which was reduced by muscarinic blockade, suggesting bidirectional modulation by changes in muscarinic activation. However, the effect of muscarinic blockade was not overcome by enhancing the activation of M1 mAChRs at a dose that restores memory deficits in prion mice.

• Item Type: Thesis (PhD)
• Qualification Level: Doctoral
• Subjects: R Medicine > RC Internal medicine > RC0321 Neuroscience. Biological psychiatry. Neuropsychiatry
• Colleges/Schools: College of Medical Veterinary and Life Sciences > School of Psychology & Neuroscience
• Supervisor's Name: Riddell, Professor John, Bradley, Dr. Sophie, Tobin, Professor Andrew and Phillips, Dr Keith
• Date of Award: 2024
• Depositing User: Theses Team
• Unique ID: glathesis:2024-84634
• Copyright: Copyright of this thesis is held by the author.
• Date Deposited: 24 Oct 2024 15:36
• Last Modified: 30 Oct 2024 09:55
• Thesis DOI: 10.5525/gla.thesis.84634
• URI: https://theses.gla.ac.uk/id/eprint/84634