Alzheimer?s disease (AD) causes dementia due to progressive neurodegeneration. This becomes detrimental to a person's ability to function independently. Fragmented sleep?wake patterns, daily cycles of confusion and agitation, and disorganized physiological rhythms are commonly observed in AD. These are also hallmarks of impaired circadian rhythms. In healthy individuals, synchronization of biological rhythms to the day/night cycle ensures optimal physiological and behavioral responses at appropriate times. A process, termed entrainment, aligns the molecular clock machinery in the suprachiasmatic nucleus (SCN), the central master circadian clock, using predictable daily environmental cues (zeitgebers). For mammals, the most dominant zeitgeber is light. However, other cues such as availability of food, social interactions or physical exercise also influence the phase of the SCN. Two of the most robust non-photic entrainment cues are regular daily availability of food (time restricted feeding or TRF) or exercise (time restricted exercise or TRE). In conjunction with light cycle, these types of time restricted schedules strengthen the periodicity of circadian clocks. Do impaired circadian rhythms hasten AD progression? Indeed, circadian rhythm defects often precede the onset of memory problems in AD, leading to our hypothesis that strengthening circadian clock output will ameliorate or slow the onset and progression of AD symptoms. In this application, we will use TRE, TRF or both of these restriction schedules simultaneously (TRE/F) to generate high amplitude behavioral and physiological circadian rhythms to revert the deleterious effects of AD-like pathology in 3xTg-AD mice. To this end, we will generate separate cohorts of 2-, 6- and 15-month old 3xTg-AD mice and place them on one of the three time restricted schedules and assess the impact of these treatments on their metabolism and physiology (Aim 1), learning and memory (Aim 2), and AD-like pathology (Aim 3).
In Aim 1, we will assess whether any of these schedules improve general activity pattern, energy utilization, glucose intolerance, insulin insensitivity and impaired gluconeogenesis in this AD model.
In Aim 2, we will determine if these circadian clock strengthening treatments diminish age-dependent cognitive decline in novel-object recognition or Morris water maze assays.
In Aim 3, we will monitor the extent of AD-like pathology to ascertain whether the improved metabolism and cognitive abilities are paralleled by decreased levels of neuroinflamation, amyloid-? (A?) deposition or intracellular hyperphosphorylated tau aggregation. If proven impactful, synchronization of biological rhythms to the proper phase of the day using time restricted eating and exercise is readily implementable for AD patients and people with high-risk of developing the disease.

Public Health Relevance

Alzheimer?s disease (AD) is a progressive brain disorder and is the leading cause of dementia. Necessities of modern society put immense pressure on human physiology by forcing incongruity between endogenous circadian rhythms and environmental cycles, which worsens a range of health issues including AD. This administrative supplement aims to demonstrate that enforcement of robust circadian rhythms can slow down or even reverse pathology, metabolism and cognitive decline associated with AD providing unique therapeutic strategies to improve the health of AD patients.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Neuroendocrinology, Neuroimmunology, Rhythms and Sleep Study Section (NNRS)
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Sesma, Michael A
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University of Virginia
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United States
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