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Time-restricted feeding reverses Alzheimer’s symptoms in mice, offers latest hope for accessible treatment

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Time-restricted feeding reverses Alzheimer’s symptoms in mice, offers latest hope for accessible treatment

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

Background

AD is a neurodegenerative disease related to the buildup of phosphorylated tau (pTau) and β-amyloid (Aβ) proteins within the brain. Most AD patients experience disturbed circadian rhythmicity, which is outstanding through their altered sleep/wake cycles because of difficulties falling and staying asleep.

Many AD patients also exhibit behavioral changes, resembling confusion within the evening, which is known as sundowning. These symptoms are related to decreased survival or nursing home placement.

Several studies have shown that circadian alterations in AD manifest earlier within the disease progression, which can aggravate its pathology. Preclinical studies linked to AD have shown that poor circadian activity patterns increase the risks of dementia and precede cognitive malfunction. So far, the underlying mechanism that links circadian dysregulation with AD prognosis stays elusive.

Based on well-regulated transcriptional programs, the circadian rhythm coordinates the each day temporal organization of physiology and behavior. Cell-autonomous clocks are present in various regions of the brain, particularly within the frontal cortex and hippocampus. A misalignment of this clock occurs because of risk aspects linked to AD, resembling 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. Moreover, this condition manifests as impaired cortical connectivity, behavioral abnormalities, and weakened memory. These observations strongly indicate how alterations within the circadian clock impact neuronal viability and cognitive function.

Lately, modulation of the circadian clock, particularly the each day feed/fast cycle, has been explored as a therapeutic approach. For instance, a mouse model of Huntington’s disease has demonstrated the importance of time-restricted feeding (TRF) in improving motor performance, sleep/wake cycles, and inflammation. Nevertheless, the underlying mechanism by which TRF induces useful outcomes is poorly understood.

In regards to the study

The present study identifies progressive circadian disruptions within the APP23 transgenic (TG) mouse model of AD, which exhibit altered behavioral circadian rhythms, excessive wakefulness, and hyperactivity. This mouse model showed significant changes within the expression pattern of many genes linked to AD pathology and neuroinflammation within the hippocampus. 

The present study used two mouse models of AD to evaluate whether circadian intervention based on TRF on the early disease stage can alleviate transcriptional alterations, improve behavior, and ameliorate pathology. 

Study findings

The present 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 related to AD and neuroinflammation, which enabled memory improvements.

The experimental findings indicate that TRF can alter the trajectory of AD by slowing its progression. This commentary was based on reduced plaque load, increased Aβ42 clearance, and a slower rate of amyloid deposition. The circadian-modulating interventions enabled a rise 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 within the hippocampus that controls sleep, motivated behavior, and excitability. Several AD mouse models revealed reduced orexin and its receptors, which ends up in sleep disturbances and behavioral issues.

There was no change in APP23 TG mice in response to light, thus implying that circadian impairments weren’t influenced by light input deficits. Nevertheless, a sturdy change in transcriptomics and behavior was observed in response to TRF. Furthermore, TRF restored glycosylation, vesicle trafficking, lipid and cholesterol dynamics, protein degradation, Aβ clearance, inflammation, and neuroglial functions, all of that are impacted by AD pathology.

Bmi1 was identified as the important thing regulator of genes altered by TRF in APP23 TG mice with AD. Bmi1 activity is related to the regulation of histone H2A mono-ubiquitination, which is affected by epigenetic aspects. Moreover, TRF increased Bmi1 levels by inhibiting downstream targets Stra6Nfatc1, and Tlr2 and induction of Npy

Conclusions

The present study is the primary to make use of AD models to show that TRF enables circadian modulation, which alters crucial pathways that trigger neurodegeneration. The degree of TRF-driven changes in hippocampal gene expression, particularly people who influence AD pathogenesis and circadian disruption, may determine the breadth of the advantages of the intervention. Taken together, these findings emphasize the therapeutic potential of TRF in AD progression.

 

Journal reference:

  • 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

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