The shared molecular mechanisms underlying aging of the brain, major depressive disorder, and Alzheimer's disease: The role of circadian rhythm disturbances

Abstract

An association with circadian clock function and pathophysiology of aging, major depressive disorder (MDD), and Alzheimer's disease (AD) is well established and has been proposed as a factor in the development of these diseases. Depression and changes in circadian rhythm have been increasingly suggested as the two primary overlapping and interpenetrating changes that occur with aging. The relationship between AD and depression in late life is not completely understood and probably is complex. Patients with major depression or AD suffer from disturbed sleep/wake cycles and altered rhythms in daily activities. Although classical monoaminergic hypotheses are traditionally proposed to explain the pathophysiology of MDD, several clinical and preclinical studies have reported a strong association between circadian rhythm and mood regulation. In addition, a large body of evidence supports an association between disruption of circadian rhythm and AD. Some clock genes are dysregulated in rodent models of depression. If aging, AD, and MDD share a common biological basis in pathophysiology, common therapeutic tools could be investigated for their prevention and treatment. Nitro-oxidative stress (NOS), for example, plays a fundamental role in aging, as well as in the pathogenesis of AD and MDD and is associated with circadian clock disturbances. Thus, development of therapeutic possibilities with these NOS-related conditions is advisable. This review describes recent findings that link disrupted circadian clocks to aging, MDD, and AD and summarizes the experimental evidence that supports connections between the circadian clock and molecular pathologic factors as shared common pathophysiological mechanisms underlying aging, AD, and MDD.