Alterations of Clock Gene RNA Expression in Brain Regions of a Triple Transgenic Model of Alzheimer’s Disease

Abstract

A disruption to circadian rhythmicity and the sleep/wake cycle constitutes a major feature of Alzheimer’s disease (AD). The maintenance of circadian rhythmicity is regulated by endogenous clock genes and a number of external Zeitgebers, including light. This study investigated the light induced changes in the expression of clock genes in a triple transgenic model of AD (3×Tg-AD) and their wild type littermates (Non-Tg). Changes in gene expression were evaluated in four brain areas¾suprachiasmatic nucleus (SCN), hippocampus, frontal cortex and brainstem¾of 6- and 18-month-old Non-Tg and 3×Tg-AD mice after 12 h exposure to light or darkness. Light exposure exerted significant effects on clock gene expression in the SCN, the site of the major circadian pacemaker. These patterns of expression were disrupted in 3×Tg-AD and in 18-month-old compared with 6-month-old Non-Tg mice. In other brain areas, age rather than genotype affected gene expression; the effect of genotype was observed on hippocampal Sirt1 expression, while it modified the expression of genes regulating the negative feedback loop as well as Rorα, Csnk1ɛ and Sirt1 in the brainstem. In conclusion, during the early development of AD, there is a disruption to the normal expression of genes regulating circadian function after exposure to light, particularly in the SCN but also in extra-hypothalamic brain areas supporting circadian regulation, suggesting a severe impairment of functioning of the clock gene pathway. Even though this study did not demonstrate a direct association between these alterations in clock gene expression among brain areas with the cognitive impairments and chrono-disruption that characterize the early onset of AD, our novel results encourage further investigation aimed at testing this hypothesis.

D‐Ser2‐oxyntomodulin ameliorated Aβ31‐35‐induced circadian rhythm disorder in mice

“…The rhythmic oscillation of the circadian clock gene in the hippocampus is called the subordinate oscillator of SCN, and Aβ induces the degradation of BMAL1 protein, which leads to the destruction of Per2 protein and mRNA oscillation . Rhythmic expression of clock genes such as Bmal1, Clock, Per, and Cry in the hippocampus of 3 × Tg‐AD mice is significantly impaired . Some studies have detected gene rhythm changes once every 6 hours .…”

Moving to the Rhythm with Clock (Circadian) Genes, Autophagy, mTOR, and SIRT1 in Degenerative Disease and Cancer

“…In regards to the control of circadian rhythm, SIRT1 may be involved with altered circadian rhythm function that affects the development of disorders such as Alzheimer's disease (131). Increased SIRT1 activity with a disruption in circadian rhythm also may result in increased susceptibility to mammary carcinogenesis (132).…”

Novel Treatment Strategies for the Nervous System: Circadian Clock Genes, Non-coding RNAs, and Forkhead Transcription Factors

“…Circadian rhythm clock genes have a significant role in the nervous system and with programmed cell death (9, 113) (Figure 1). The mammalian circadian clock resides in the suprachiasmatic nucleus (SCN) located above the optic chiasm and receives light input from photosensitive ganglion cells in the retina.…”

“…SIRT1 has been associated with altered circadian rhythm function that affects the development of disorders such as AD (113). SIRT1 control of circadian rhythm and melatonin also may affect glucose tolerance and DM (115) as well as inflammation during obesity (154).…”

“…SIRT1 pathways are involved in vascular survival and senescence (88, 152, 161), atherosclerosis (162–166), lifespan extension (4, 167–169), diabetic retinopathy (170), cellular metabolism and DM (14, 17, 20, 115, 145, 171, 172), oxidative stress pathways (58, 148, 173–179), and neuronal survival and cognition (11, 113, 180–183). …”