Brain Star Award winner Christopher Daniel Morrone

Brain cleaning deficiencies are linked to sleep loss at the early stages of Alzheimer’s disease

Autophagy involves the recycling of the cell’s own components, such as damaged proteins, and is a highly regulated mechanism that is essential for maintaining cellular health. Research done by Christopher Daniel Morrone working at the Centre for Addiction and Mental Health is the first to describe autophagic dysfunction in neurons responsible for sleep-wake control and sleep loss as interactive disease mechanisms in Alzheimer’s disease. 

Sleep loss is increasingly recognized as a commonality across most brain disorders including as a risk factor for Alzheimer’s disease and related dementias. Alzheimer’s disease is a proteinopathy, that is a disease in which malformed proteins accumulate abnormally in the brain, forming toxic aggregates or plaques. The work described here provides experimental evidence for a positive-feedback-loop between sleep and autophagy as a driver of the Alzheimer’s disease symptoms.

In this work, the researchers employed a mouse model of Alzheimer’s disease with accumulation of two proteins, called β-amyloid and tau, to elucidate the sleep-autophagy link. Early disruption of REM sleep and neuronal dysfunction in a brain region called the hippocampus preceded cognitive decline in the Alzheimer’s disease mice. Interestingly, autophagic impediment in the cytoplasm of sleep-wake neurons was robust from the early-stage and progressed over age, coinciding with declining sleep quality. This selective vulnerability of sleep-wake neurons to failed autophagic cleaning preceded the formation of β-amyloid plaques in the sleep regions – the hypothalamus and locus coeruleus. These autophagic changes were more robust than what was seen in the more plaque-bearing brain regions classically associated with Alzheimer’s disease – hippocampus, entorhinal cortex and prefrontal cortex. This work also highlighted sex differences inherent to Alzheimer’s disease progression including a more rapid decline of sleep in the female Alzheimer’s disease mice, and a greater cognitive impairment in males linked to uncleared autophagic inclusions in neurons known to regulate learning and memory.

Finally, the researchers showed 1) slower brain wave activity similar to sleepiness during learning in Alzheimer’s disease mice, 2) that disrupting sleep in control mice could mimic Alzheimer’s disease including protein accumulation and dysfunctional sleep-wake patterns, and 3) that activating autophagy using drugs could improve sleep recovery after disruption.

There is an emerging need to identify treatable disease mechanisms and risk factors for neurodegeneration and Alzheimer’s disease. Sleep loss is increasingly recognized as a commonality across most brain disorders including as a risk factor for Alzheimer’s disease and related dementias, Parkinson’s disease, and as a diagnostic criteria for Major Depression. Addressing sleep disturbances can mitigate the risk, progression and symptomatic profile across brain disorders, and as this work demonstrates, can directly influence the key pathologies in neurodegeneration.

Given the relationship of impaired sleep with autophagic impediment, which is described in this manuscript, promoting healthy sleep is a key therapeutic target for these disorders. Importantly, sleep is modifiable through clinically available behavioural and pharmacological approaches, including new classes of drugs gaining traction in Alzheimer’s disease and sleep disorders. This work additionally highlights the importance of understanding sex-specific mechanisms in Alzheimer’s disease treatment.

About Christopher Daniel Morrone

I am a Postdoctoral Fellow with the Brain Health Imaging Centre at the Centre for Addiction and Mental Health (CAMH) and a Lecturer at the University of Toronto. I completed my undergraduate degree at the University of Toronto in Neuroscience. I received my PhD in the Department of Laboratory Medicine and Pathobiology at University of Toronto and Sunnybrook Research Institute focused on cognitive resilience and therapeutic approaches for Alzheimer’s disease. This work was supported by my Canadian Institutes of Health Research (CIHR) fellowship and Ontario Graduate Scholarships.

My postdoctoral research centres on sleep as a modifiable risk factor for dementia and biomarkers including PET imaging and EEG. I have received prestigious fellowships from CIHR, BrightFocus Foundation and the CAMH Discovery Fund. My research and teaching goals are to explore brain-behaviour relationships in dementia, discover selective neuronal and regional vulnerabilities, and identify new therapeutic approaches for Alzheimer’s disease and related dementias.

Sources of funding

Funding support was provided from the donors of Alzheimer’s Disease Research, a program of BrightFocus Foundation (A2022016F; CDM), CAMH Discovery Fund (CDM) and National Institutes of Health (RF1-AG080781 – WHY).