Abstract
Introduction:Dementia and cognitive loss impact a significant proportion of the global population and present almost insurmountable challenges for treatment since they stem from multifactorial etiologies. Innovative avenues for treatment are highly warranted.Methods and results:Novel work with biological clock genes that oversee circadian rhythm may meet this critical need by focusing upon the pathways of the mechanistic target of rapamycin (mTOR), the silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae) (SIRT1), mammalian forkhead transcription factors (FoxOs), the growth factor erythropoietin (EPO), and the wingless Wnt pathway. These pathways are complex in nature, intimately associated with autophagy that can maintain circadian rhythm, and have an intricate relationship that can lead to beneficial outcomes that may offer neuroprotection, metabolic homeostasis, and prevention of cognitive loss. However, biological clocks and alterations in circadian rhythm also have the potential to lead to devastating effects involving tumorigenesis in conjunction with pathways involving Wnt that oversee angiogenesis and stem cell proliferation.Conclusions:Current work with biological clocks and circadian rhythm pathways provide exciting possibilities for the treating dementia and cognitive loss, but also provide powerful arguments to further comprehend the intimate and complex relationship among these pathways to fully potentiate desired clinical outcomes.
Highlights
Innovative work with biological clock genes that oversee circadian rhythm can offer new strategies for the treatment of dementia that employ the pathways of the mechanistic target of rapamycin, the silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae) (SIRT1), mammalian forkhead transcription factors (FoxOs), the growth factor erythropoietin (EPO), and the wingless Wnt/β-catenin pathway
Studies suggest that a basal circadian rhythm that modulates autophagy and mechanistic target of rapamycin (mTOR) pathways involving mTOR Complex 1 and mTOR Complex 2 may be necessary to prevent cognitive decline and cellular toxicity with amyloid deposition. mTOR holds an inverse relationship with SIRT1 and these pathways may be necessary to support circadian components CLOCK and BMAL1 to prevent loss of cellular metabolic homeostasis
Given the need for novel strategies directed against memory loss and dementia, exciting new avenues of development are focusing upon biological clock mechanisms and include the pathways of the mechanistic target of rapamycin, its associated pathways of mTOR Complex 1, mTOR Complex 2, the silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae) (SIRT1), mammalian forkhead transcription factors (FoxOs), the growth factor erythropoietin (EPO), and the wingless pathway of Wnt pathway (Fig. 1)
Summary
Current attempts to treat dementia such as with cholinesterase inhibitors may lead to a decrease in the presenting symptoms but do not block the progression of the disease, such as in AD [27, 45, 47, 48]. As part of the biological clock gene group, members of the basic helix-loop-helix-PAS (PeriodArnt-Single-minded) transcription factor family, that include CLOCK and BMAL1 [104], control gene expression of Cryptochrome (Cry and Cry2) and Period (Per, Per, and Per3) [6, 78, 84, 86, 105,106,107]. With neurodegeneration and aging studies, experimental studies with Parkinson’s disease (PD) using 6-hydroxydopamine (6-OHDA) during chronic treatment with levodopa show depressed levels of BMAL1 and RORα, indicating that memory loss in PD patients may be a result of medication that alters circadian rhythm clock genes [106]. In experimental studies AD using mice, significant alterations have been observed in RNA clock gene expression that may suggest a dysfunction in the clock pathways during cognitive loss [110]
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