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Chemical changes in brain cells caused by disturbances in the body’s day-night cycle may lead to the learning and memory loss associated with Alzheimer’s disease, according to a University of California, Irvine (UCI) study.
People with Alzheimer’s often have problems with sleeping or may experience changes in their slumber schedule. Scientists do not completely understand why these disturbances occur.
“The issue is whether poor sleep accelerates the development of Alzheimer’s disease or vice versa,” said UCI biomedical engineering professor Gregory Brewer, affiliated with UCI’s Institute for Memory Impairments and Neurological Disorders. “It’s a chicken-or-egg dilemma, but our research points to disruption of sleep as the accelerator of memory loss.”
Inducing jet lag in mice causes low glutathione levels
To examine the link between learning and memory and circadian disturbances, his team altered normal light-dark patterns, with an eight-hour shortening of the dark period every three days for two groups of mice: young mouse models of Alzheimer’s disease (mice genetically modified to have AD symptoms) and normal mice.
The resulting jet lag greatly reduced activity in both sets of mice. The researchers found that in water maze tests, the AD mouse models had significant learning impairments that were absent in the AD mouse models not exposed to light-dark variations or in normal mice with jet lag. However, memory three days after training was impaired in both types of mice.
In follow-up tissue studies, they saw that jet lag caused a decrease in glutathione levels in the brain cells of all the mice. But these levels were much lower in the AD mouse models and corresponded to poor performance in the water maze tests. Glutathione is a major antioxidant that helps prevent damage to essential cellular components.
Glutathione deficiencies produce redox changes in brain cells. Redox reactions involve the transfer of electrons, which leads to alterations in the oxidation state of atoms and may affect brain metabolism and inflammation.
Brewer pointed to the accelerated oxidative stress as a vital component in Alzheimer’s-related learning and memory loss and noted that potential drug treatments could target these changes in redox reactions.
“This study suggests that clinicians and caregivers should add good sleep habits to regular exercise and a healthy diet to maximize good memory,” he said.
Study results appear online in the Journal of Alzheimer’s Disease.
AD has emerged as a global public health issue, currently estimated to affect 4.4% of persons 65 years old and 22% of those aged 90 and older, with an estimated 5.4 million Americans affected, according to the paper.
Abstract of Circadian Disruption Reveals a Correlation of an Oxidative GSH/GSSG Redox Shift with Learning and Impaired Memory in an Alzheimer’s Disease Mouse Model
It is unclear whether pre-symptomatic Alzheimer’s disease (AD) causes circadian disruption or whether circadian disruption accelerates AD pathogenesis. In order to examine the sensitivity of learning and memory to circadian disruption, we altered normal lighting phases by an 8 h shortening of the dark period every 3 days (jet lag) in the APPSwDI NOS2–/– model of AD (AD-Tg) at a young age (4-5 months), when memory is not yet affected compared to non-transgenic (non-Tg) mice. Analysis of activity in 12-12 h lighting or constant darkness showed only minor differences between AD-Tg and non-Tg mice. Jet lag greatly reduced activity in both genotypes during the normal dark time. Learning on the Morris water maze was significantly impaired only in the AD-Tg mice exposed to jet lag. However, memory 3 days after training was impaired in both genotypes. Jet lag caused a decrease of glutathione (GSH) levels that tended to be more pronounced in AD-Tg than in non-Tg brains and an associated increase in NADH levels in both genotypes. Lower brain GSH levels after jet lag correlated with poor performance on the maze. These data indicate that the combination of the environmental stress of circadian disruption together with latent stress of the mutant amyloid and NOS2 knockout contributes to cognitive deficits that correlate with lower GSH levels.