A recent Cell Metabolism study explores the therapeutic potential of circadian-modulating interventions to treat Alzheimer's disease (AD).
Study: Circadian modulation by time-restricted feeding rescues brain pathology and improves memory in mouse models of Alzheimer's disease. Image Credit: VGstockstudio / Shutterstock.com
AD is a neurodegenerative disease associated with the accumulation of phosphorylated tau (pTau) and β-amyloid (Aβ) proteins in the brain. Most AD patients experience disturbed circadian rhythmicity, which is prominent through their altered sleep/wake cycles due to difficulties falling and staying asleep.
Many AD patients also exhibit behavioral changes, such as confusion in the evening, which is referred to as sundowning. These symptoms are associated with decreased survival or nursing home placement.
Several studies have shown that circadian alterations in AD manifest earlier in the disease progression, which may aggravate its pathology. Preclinical studies linked to AD have shown that poor circadian activity patterns increase the risks of dementia and precede cognitive malfunction. To date, the underlying mechanism that links circadian dysregulation with AD prognosis remains elusive.
Based on well-regulated transcriptional programs, the circadian rhythm coordinates the daily temporal organization of physiology and behavior. Cell-autonomous clocks are present in various regions of the brain, particularly in the frontal cortex and hippocampus. A misalignment of this clock occurs due to risk factors linked to AD, such as inflammation, diabetes, sleep disorders, and cardiovascular diseases.
Deletion of the core circadian clock genes Bmal1 and Per1 in mice triggers oxidative damage and synaptic degeneration. Furthermore, this condition manifests as impaired cortical connectivity, behavioral abnormalities, and weakened memory. These observations strongly indicate how alterations in the circadian clock impact neuronal viability and cognitive function.
In recent years, modulation of the circadian clock, particularly the daily feed/fast cycle, has been explored as a therapeutic approach. For example, a mouse model of Huntington's disease has demonstrated the significance of time-restricted feeding (TRF) in improving motor performance, sleep/wake cycles, and inflammation. However, the underlying mechanism by which TRF induces beneficial outcomes is poorly understood.
About the study
The current study identifies progressive circadian disruptions in the APP23 transgenic (TG) mouse model of AD, which exhibit altered behavioral circadian rhythms, excessive wakefulness, and hyperactivity. This mouse model showed significant changes in the expression pattern of many genes linked to AD pathology and neuroinflammation in the hippocampus.
The current study used two mouse models of AD to assess whether circadian intervention based on TRF at the early disease stage can alleviate transcriptional alterations, improve behavior, and ameliorate pathology.
The current study reports the pleiotropic effects of TRF treatment in altering sleep and behavior patterns. The authors also enabled normalization of hippocampal gene expression in specific pathways associated with AD and neuroinflammation, which enabled memory improvements.
The experimental findings indicate that TRF can alter the trajectory of AD by slowing its progression. This observation was based on reduced plaque load, increased Aβ42 clearance, and a slower rate of amyloid deposition. The circadian-modulating interventions enabled an increase in total sleep and alleviated sundowning-like hyperactivity.
APP23 TG mice without diurnal oscillation in genes exhibited hyperexcitability and reduced sleep. Orexin is a neurotransmitter expressed in the hippocampus that controls sleep, motivated behavior, and excitability. Several AD mouse models revealed reduced orexin and its receptors, which leads to sleep disturbances and behavioral issues.
There was no change in APP23 TG mice in response to light, thus implying that circadian impairments were not influenced by light input deficits. However, a robust change in transcriptomics and behavior was observed in response to TRF. Moreover, TRF restored glycosylation, vesicle trafficking, lipid and cholesterol dynamics, protein degradation, Aβ clearance, inflammation, and neuroglial functions, all of which are impacted by AD pathology.
Bmi1 was identified as the key regulator of genes altered by TRF in APP23 TG mice with AD. Bmi1 activity is associated with the regulation of histone H2A mono-ubiquitination, which is affected by epigenetic factors. Additionally, TRF increased Bmi1 levels by inhibiting downstream targets Stra6, Nfatc1, and Tlr2 and induction of Npy.
The current study is the first to use AD models to demonstrate that TRF enables circadian modulation, which alters crucial pathways that trigger neurodegeneration. The degree of TRF-driven changes in hippocampal gene expression, particularly those that influence AD pathogenesis and circadian disruption, may determine the breadth of the benefits of the intervention. Taken together, these findings emphasize the therapeutic potential of TRF in AD progression.
- Whittaker, D. S., Akhmetova, L., Carlin, D., et al. (2023) Circadian modulation by time-restricted feeding rescues brain pathology and improves memory in mouse models of Alzheimer’s disease. Cell Metabolism. doi:10.1016/j.cmet.2023.07.014