The impact of sleep-wake interventions on neuropathology and cognition in a mouse model of dementia

Sleep-wake disturbances are a common neuropsychiatric symptom of dementia, including Alzheimer’s disease (AD) and frontotemporal dementia (FTD). However, no standard-of-care therapies are currently systematically prescribed to address these symptoms. Previous studies showed that sleep disruption is a predictor of cognitive impairment and can exacerbate disease progression in AD patients, whilst enhanced sleep can attenuate both cognitive deficits and underlying pathology in preclinical models of dementia. In this thesis, we investigated the impact of sleep-promoting interventions on neuropathology, sleep-wake disturbances and cognitive decline in the rTg4510 mouse model of dementia. We first characterised specific molecular pathways in 6-months-old mice and confirmed sleep and behavioural deficits of this model compared to wild-type controls. Then, we assessed the effect of chronic administration of two drugs: trazodone, a multifunctional drug commonly used off-label as a hypnotic, and a compound with a similar mechanism of action, compared to placebo. Both drugs transiently delayed tau pathology and reduced microglial activation and expression of the microglial Nod-like receptor protein 3 (NLRP3) inflammasome in male rTg4510 mice after 9-weeks. Other pathways involved in microglial activation and tau propagation, such as P38 mitogen-activated protein kinase (P38 MAPK) signalling and components of the Unfolded Protein Response (UPR), were also transiently inhibited by these treatments. In parallel, we explored the impact of chronic treatment on sleep, as well as olfactory and spatial memory. Chronic trazodone treatment rescued electroencephalography (EEG) slowing disturbances and increased rapid-eye movement sleep (REMS) duration, suggesting it can successfully reverse features typically found in AD patients. Trazodone also attenuated early olfactory memory deficits, which was correlated with changes observed during REMS. In addition, voluntary physical activity was assessed as a potential non-pharmacological intervention to treat tauopathies and related cognitive impairment during moderate to severe stages of disease in rTg4510 mice. However, no positive effect was observed after 5-weeks. Altogether, our data provide novel insights to the beneficial role of multitarget pharmacology on underlying neuropathology and related symptomology in AD and other tauopathies