Circadian Clock Gene Expression in Brain Regions of Alzheimer ’s Disease Patients and Control Subjects

Abstract

Circadian oscillators have been observed throughout the rodent brain. In the human brain, rhythmic expression of clock genes has been reported only in the pineal gland, and little is known about their expression in other regions. The investigators sought to determine whether clock gene expression could be detected and whether it varies as a function of time of day in the bed nucleus of the stria terminalis (BNST) and cingulate cortex, areas known to be involved in decision making and motivated behaviors, as well as in the pineal gland, in the brains of Alzheimer's disease (AD) patients and aged controls. Relative expression levels of PERIOD1 (PER1 ), PERIOD2 (PER2), and Brain and muscle Arnt-like protein-1 (BMAL1) were detected by quantitative PCR in all 3 brain regions. A harmonic regression model revealed significant 24-h rhythms of PER1 in the BNST of AD subjects. A significant rhythm of PER2 was found in the cingulate cortex and BNST of control subjects and in all 3 regions of AD patients. In controls, BMAL1 did not show a diurnal rhythm in the cingulate cortex but significantly varied with time of death in the pineal and BNST and in all 3 regions for AD patients. Notable differences in the phase of clock gene rhythms and phase relationships between genes and regions were observed in the brains of AD compared to those of controls. These results indicate the presence of multiple circadian oscillators in the human brain and suggest altered synchronization among these oscillators in the brain of AD patients.

The Circadian System in Alzheimer’s Disease: Disturbances, Mechanisms, and Opportunities

“…Both the BNST and the cingulate cortex have previously been shown to express rhythmic clock genes (10,53). Similar peak times for PER1 and PER2 in control subjects in the active phase were reported, whereas BMAL1 was shown to peak in the night (52). Interestingly, PERs and BMAL1 displayed significant 24-hour rhythmicity in the brains of AD patients.…”

“…Interestingly, PERs and BMAL1 displayed significant 24-hour rhythmicity in the brains of AD patients. However, a state of desynchrony in oscillation between cortex, pineal gland, and the BNST in AD patients was found, possibly caused by the degeneration of the SCN cells in AD brains (52). Given the roles of the BNST and cingulate cortex in decision-making and motivated behaviors and the position of the pineal gland as a major output of the SCN, abnormal rhythms in these brain regions or lack of coordination between them might contribute to cognitive and sleep-wake deficits in AD patients.…”

Sleep and Cognitive Decline: A Strong Bidirectional Relationship. It Is Time for Specific Recommendations on Routine Assessment and the Management of Sleep Disorders in Patients with Mild Cognitive Impairment and Dementia

“…The rhythmic expression of BMAL1, CRY1 and PER1 in the cingulate cortex, bed nucleus of the stria terminalis and/or pineal gland appears to be lost in clinical and preclinical AD patients [21,22,28] . On the other hand, Tseng et al [29] examined the expression of PER1 in circulating leukocytes across different sleep phases in healthy subjects and in MCI and AD patients, but found no differences.…”

Circadian patterns of gene expression in the human brain and disruption in major depressive disorder

“…Previous analyses of human tissues involved easily accessible oral mucosa (14), skin biopsies (15), hair follicle cells (16), and cultured cell lines (17,18). Some human postmortem brain studies have focused on a limited number of candidate clock genes (19)(20)(21), but the overall orchestration of circadian regulation of gene expression in the human brain and its potential dysregulation in major depression remained unknown.…”