The Rhythmicity of Clock Genes is Disrupted in the Choroid Plexus of the APP/PS1 Mouse Model of Alzheimer’s Disease

Abstract

Background: The choroid plexus (CP), which constitutes the blood-cerebrospinal fluid barrier, was recently identified as an important component of the circadian clock system. Objective: The fact that circadian rhythm disruption is closely associated to Alzheimer’s disease (AD) led us to investigate whether AD pathology can contribute to disturbances of the circadian clock in the CP. Methods: For this purpose, we evaluated the expression of core-clock genes at different time points, in 6- and 12-month-old female and male APP/PS1 mouse models of AD. In addition, we also assessed the effect of melatonin pre-treatment in vitro before amyloid-β stimulus in the daily pattern of brain and muscle Arnt-like protein 1 (Bmal1) expression. Results: Our results showed a dysregulation of circadian rhythmicity of Bmal1 expression in female and male APP/PS1 transgenic 12-month-old mice and of Period 2 (Per2) expression in male mice. In addition, a significant circadian pattern of Bmal1 was measured the intermittent melatonin pre-treatment group, showing that melatonin can reset the CP circadian clock. Conclusion: These results demonstrated a connection between AD and the disruption of circadian rhythm in the CP, representing an attractive target for disease prevention and/or treatment.

Choroid Plexus in Alzheimer’s Disease—The Current State of Knowledge

“…The circadian rhythm of CP in mouse AD is unregulated, as shown by the aberrant oscillations in the expression of clock genes. The circadian rhythmicity was recovered when a CP cell line was treated with melatonin in the presence of Aβ [ 91 ]. The same group of researchers showed the impact of circadian rhythm on the secretion of Aβ scavengers—apoliprotein J (ApoJ) and TTR—in non-transgenic rat explants, with a clear pattern of fluctuations in the expression of those proteins [ 92 ].…”

Choroid plexus function in neurological homeostasis and disorders: The awakening of the circadian clocks and orexins

“…First, CP-related neurological impairment may be associated with loss of rhythmicity and synchronicity of CP clock genes. 108 In vitro studies of CP cells from AD mice demonstrate that there is a connection between AD and disruption to circadian rhythms within the CP. 91 , 108 This may result in a disconnect between CP and glymphatic function, resulting in sub-optimal clearance from the CSF, and increased build-up of amyloid-β and tau.…”

Importance of Bmal1 in Alzheimer's disease and associated aging‐related diseases: Mechanisms and interventions

“…Intermittent administration of melatonin can reset the daily pattern of Bmal1 expression (Furtado et al, 2020). Furthermore, endogenous and exogenous melatonin ameliorates diabetes and related metabolic dysfunction by regulating insulin secretion and protecting against ROS (Espino et al, 2019).…”

“…A study showed that melatonin treatment increased Bmal1 expression in the hippocampus, induced rapid remodeling of hippocampal neurons, and altered the synaptic structure in the CA1 and dentate gyrus regions, suggesting that melatonin can regulate the structural changes in hippocampal neurons through the circadian clock molecule Bmal1 (Ikeno & Nelson, 2015 ). Intermittent administration of melatonin can reset the daily pattern of Bmal1 expression (Furtado et al, 2020 ). Furthermore, endogenous and exogenous melatonin ameliorates diabetes and related metabolic dysfunction by regulating insulin secretion and protecting against ROS (Espino et al, 2019 ).…”