Harjani Tirathdas, Lavitasha; (2025) Impact of Alzheimer’s Disease Associated Peptides on Sleep-Wake State. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Sleep disturbances are an early and well recognized symptom of Alzheimer’s Disease (AD) and are also thought to contribute to disease progression. However, the underlying signalling mechanisms driving these sleep disruptions remain poorly understood. This PhD thesis investigates how amyloid beta oligomers (AOs) and P3 – an overlooked APP cleavage fragment – contribute to early AD-related sleep deficits. Using high-throughput behavioural monitoring in zebrafish larvae, I show that acute exposure to AOs disrupts sleep in a conformation- and size-dependent manner. Notably, ADDLs, a small AOs species, and P3 – both abundant in early AD – fragment sleep and reduce total sleep duration, mirroring disruptions observed in AD patients. I further identify the membrane protein Pgrmc1 and the Prion protein (Prp) as essential mediators of both ADDLs- and P3-induced sleep disturbances, revealing a shared signalling pathway. Pharmacological blockade of Prp-dependent signalling rescues these sleep deficits, offering a potential therapeutic strategy. Moreover, using whole brain mapping of prp and pgrmc1, alongside tracking of A dispersal, I identify the radial astroglia as a key site for AO and P3 signalling. To explore potential signalling alterations at the glial level, I use calcium imaging, providing the first in vivo evidence that acute AOs and P3 exposure disrupts glial calcium homeostasis. Employing sleep-wake modulating drugs to disentangle sleep amount from sleep pressure, I demonstrate that glial calcium levels are closely associated with alterations in sleep pressure. I propose that AOs and P3 disrupt sleep regulation by impairing glial calcium accumulation, thereby interfering with sleep pressure integration. Overall, these findings establish P3 as a novel contributor to AD-related sleep disturbances, uncover a mechanism by which AOs and P3 acutely alter glial calcium dynamics, and highlight promising targets for early therapeutic intervention.

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