Ketogenic diet prevents chronic sleep deprivation-induced Alzheimer’s disease by inhibiting iron dyshomeostasis and promoting repair via Sirt1/Nrf2 pathway

Abstract

Sleep deprivation (SD) is one of the main risk factors for Alzheimer’s disease (AD), but the underlying mechanism is still unclear. Ketogenic diet (KD) has been shown widely neuroprotective effects but less known about its effect on SD-induced AD. In the present study, a continuous 21 days SD mouse model with or without KD was established. The changes of cognitive function, pathological hallmarks of AD, ferroptosis, and intracellular signal pathways in mice were detected by Morris water maze, ThS staining, diaminobenzidine (DAB)-enhanced Perls’ stain, antioxidant assay, immuno-histochemistry, and western blot. The results showed that KD can prevent the cognitive deficiency, amyloid deposition and hyperphosphorylated tau induced by chronic SD. Analysis of ferroptosis revealed that KD can inhibit iron dyshomeostasis by down-regulating the expression of TfR1 and DMT1 and up-regulating the expression of FTH1, FPN1. Meanwhile, KD alleviated oxidative stress with elevated xCT/GPX4 axis, FSP1 and reduced MDA. In addition, KD could promote neuronal repair by enhancing BDNF and DCX. Further studies demonstrated that KD activated Sirt1/Nrf2 signaling pathway in the hippocampus in SD-exposed mice. Our finding firstly suggested that KD could prevent chronic SD-induced AD by inhibiting ferroptosis and improving the neuronal repair ability via Sirt1/Nrf2 signaling pathway.

Research progress on the effects of ketogenic diet on central nervous system diseases

“…Compared with normal people, the phenomenon of brain iron deposition is more evident in AD patients with increasing age. This further demonstrates that the phenomenon of iron deposition is inseparable from the development process of the CNS diseases [4]. Microglia are the main cells that accumulate iron ions in neurodegenerative diseases.…”

“…tau protein Abnormal phosphorylation, leading to cognitive impairment, further promotes the development of AD. If the aggregation of Aβ is reduced or prevented, the development of Alzheimer's disease can be prevented or even prevented [4]. Several investigations have discovered that AD can stop the development of AD by preventing cognitive decline, amyloid buildup, and tau hyperphosphorylation brought on by persistent SD.…”

“…However, the astrocytes were indeed the opposite, still in a state of survival [17]. Researchers measured the total iron, iron accumulation and iron transporter expression in the hippocampus of mice after ketogenic diet intervention, and found that the expression of ferritin in the hippocampus of KD experimental group was reduced compared with the control group, and iron deposition was reduced [4].…”

Farnesol Exerts Protective Effects against Chronic Sleep Deprivation‐Induced Cognitive Impairment via Activation SIRT1/Nrf2 Pathway in the Hippocampi of Adult Mice

“…[ 53 ] Other studies showed that suppressing hippocampal ferroptosis could alleviate SD‐induced memory loss. [ 13,54 ] In summary, these findings indicate that the Sirt1/Nrf2/HO‐1/Gpx4 signaling pathway is a potential therapeutic target for SD‐induced cognitive impairment.…”

Recommendations from the Medical Education Editor

“…Although ketogenic diets might seem like a social media fad, emerging science explores their role in various health conditions, including obesity, neurologic, psychiatric and sleep disorders. [5][6][7] The low-carbohydrate, high-fat diet appears to confer a neuroprotective effect; however, the mechanisms of action remain under investigation.…”