Elucidating the role of circadian-gated cognitive disruption in Alzheimer’s disease pathogenesis

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Project Abstract As the portion of the population that is aged 65 and older rapidly increases in parallel with increases in life expectancy, there is an urgent need to address the disease states that affect the elderly population. One of these—perhaps the most devastating—is Alzheimer’s disease (AD). In addition to the cognitive impairments that underlie AD, these patients suffer with dysregulation of their circadian timing system including cognition. This timing system is vital to health at the cellular level and to overall physiology; hence, circadian disruptions can have profound negative effects on health, further exacerbating the AD symptomology. Specifically, circadian- gated cognition is the inherent 24-hour cycles of regulation that underlie efficacy of learning and memory across the day. Along these lines, the goal of this work is to better understand the molecular components in the brain that mediate deterioration of circadian-gated cognition in AD. Utilizing an innovative set of approaches ranging from behavioral testing to in vivo cranial window multiphoton imaging, this work will address the following specific aims. My dissertation work thus far (Aim 1) has shown that circadian-gated cognitive deficits are present in a mouse model of rapid amyloid deposition and that there are disruptionin core clock genes that generate circadian timing may mediate these. Circadian timing regulates a plethora of cellular processes, including the functionality of the mitogen activated protein kinase (MAPK) pathway. Furthermore, the MAPK pathway is essential to circadian-gated cognitiveprocesses and its activation has been shown to be disrupted in AD. Thus, in next phase of my work (F99, Aim 2), I will test if the dysregulation of MAPK pathway activation is the mechanistic link governing disruption of circadian-gated cognition in a model of AD. In addition to profiling the disruption of MAPK activity in AD, I will attempt to restore activity of the MAPK pathway to baseline, thus rescuing circadian-gated cognition. Upon the completion of my dissertation work, I plan to complete a postdoctoral fellowship (K00, Aim 3) where I will aim to study the genetic basis of sleep in parallel with the genetic mechanisms underlying sleep dysfunction in neurodegenerative disorders. This postdoctoral work will complement my training in circadian biology and neurodegeneration ultimately providing me the necessary tools and skill to address questions regarding the interplay of sleep and circadian rhythmicity disruption in neurodegenerative.